regulation of cell proliferation and growth by angiotensin ii

Progrexs in Growrh Facror Remrch, Vol. 5. p Ill-194, 1994

Pergamon Copyright cj 1994 Elsevier Science Ltd.

Printed in Great Britain. All rights reserved G955-2235194 $26 IWI

REGULATION OF CELL PROLIFERATION AND GROWTH BY ANGIOTENSIN II

William R. HuckIe* and H. Shelton Earpt

Department of Medicine and Pharmacology UNC-Lineberger Comprehensive Cancer Center, CB 7295

University of North Carolina at Chapel Hill Chapel Hill, NC 275997295, U.S.A.

The peptide hormone angiotensin II (Angil) has clearly definedphysiologic roles as a regulator of vasomotor tone and fluid homeostasis. In addition AngIl has trophic or mitogenic effects on a variety of target tissues, including vascular smooth muscle and udrenal cells. More recent data indicate that AngIl exhibits many characteristics of the ‘classical’ peptide growth factors such as EGF/TGFa, PDGF and IGF-I. These include the capacity for local generation (‘autocrine or paracrine’ action) and the ability to stimulate tyrosine phosphorylation, to activate MAP kinases and to increase expression of nuclear proto-oncogenes. The type 1 AngII receptor, which is responsible for all known physiologic actions of AngIl, has been cloned. Activation of this receptor leads to elevated phosphoinositide hydrolysis, mobilization of intracellular Cal+ and diacylglycerol. and activation of Ca’+/calmodulin and Ca2+/phospholipid-dependent SerlThr kinases, as well as Caz+ regulated tyrosine kinases. The existence of other AngIl receptor subtypes has been postulated, but the function(s) of these sites remains unclear. In vascular smooth muscle, AngII can promote cellular hypertrophy and/or hyperplasia, depending in part on the patterns of induction of secondary factors that are known to stimulate (PDGF, IGF-1, basic FGF) or inhibit (TGF-p) mitosis. Together, these findings have suggested that AngIIplays important roles in both the normal development and pathophysiology of vascular, cardiac, renal and central nervous system tissues.

Keywords: Angiotensin II, growth factor, calcium, tyrosine kinase, vascular smooth muscle. mitosis.

*Present Address: Department of Pharmacology, Merck Research Laboratories, WP42-300, West Point. PA 19486, U.S.A.

tCorresponding author. Acknowledgements-The authors thank Alice Berry and Debra Hunter for technical assistance and Janet

Reynolds for preparation of the manuscript. We thank Dr Ronald Smith of DuPont Merck Pharmaceuticals for providing the AngII antagonists Losartan (DuP753) and PD123177. Studies performed in the authors’ laboratory were supported by grants DK31683 (HSE) and F32 DK08378 (WRH) from the National Institutes of Health.

177

178 W. R. Huckle and H. S. Earp

INTRODUCTION

The octapeptide angiotensin II (AngII) is well known as an acute regulator of vasomotor tone and fluid homeostasis. The initial isolation and structural characterization of AngII was based on these activities [1, 2].* The concept that AngII plays a key role in cardiovascular physiology is broadly supported by the efficacy of pharmacologic blockers of AngII biosynthesis as anti-hypertensive agents [4].

Over the past 15-20 years a number of observations have suggested that the actions of AngII extend beyond those of a transiently-acting vasoconstrictor and aldosterone secretogogue. In 1977 it was reported that AngII could promote the proliferation of adrenocortical cells in culture [5], a finding shortly thereafter extended to 3T3 fibroblasts [6]. Today, there is a high level of interest in long term actions of AngII and other vasoactive peptides, ranging from their possible involvement in vascular and cardiac hypertrophy to roles in renal growth and central nervous system development. These topics have been addressed in numerous recent reviews [7-191. The present review will focus on recent advances in our understanding of AngII signalling processes and on interactions of AngII with other growth factors.

BIOSYNTHESIS OF ANGII: RENIN-ANGIOTENSIN SYSTEMS

Circulating AngII is the product of a multi-step biosynthetic pathway whose components are widely distributed [20]. The protein precursor of AngII, angiotensinogen, is a 55-65 kDa or-2 globulin synthesized principally by the liver. Angiotensino- gen is cleaved by the protease renin yielding the decapeptide angiotensin-I. Renin, a product of the juxtaglomerular cells of the kidney, is secreted in response to changes in renal hemodynamics. Removal of the carboxy-terminal dipeptide of angiotensin I produces the mature octapeptide AngII (human sequence: AspArg-Val-Tyr-Ile His-ProPhe). In the context of the pressor actions of AngII, the cleavage of angiotensin I to AngII appears to be mediated largely by the zinc metalloprotease known as angiotensin-converting enzyme (ACE), which is concentrated in the endothelia of the kidney and lung [21].

In addition to this ‘classical’ pathway for generation of circulating AngII, the concept of ‘local’ renin-angiotensin systems recently has gained wider acceptance [22,23]. Studies of these systems have been facilitated by the availability of sensitive and specific probes, both genetic and immunologic, for detecting expression of pathway components in novel sites [24]. Thus evidence has been accumulated for the existence of functional AngII-generating systems in the heart [25-281, vascular smooth muscle [29,30], brain [31], kidney [32] and adrenal gland [33].

The ramifications of local renin-angiotensin systems for growth-related effects of AngII are several. The opportunity exists for locally-regulated pathways to function independently of systemic, physiologic factors that control vasomotor tone or fluid homeostasis. Indeed, regulation of growth in a self-contained, autocrine/paracrine fashion is a hallmark of those substances (e.g. TGF-a, TGF-P, FGF and PDGF) that are viewed principally as growth factors rather than endocrine agents. Both experi-

*An interesting personal retrospective on these discoveries has appeared recently [3].

Control of Growth by Angiotensin II 179

mental and clinical experience have demonstrated that treatment with ACE inhibitors can prevent or reverse cardiac hypertrophy associated with chronic hypertension [34 391. Although interpretation is complicated by the ability of ACE inhibitors also to block the degradation of bradykinin [40], part of the aforementioned cardioprotective effect of ACE inhibitors appears to occur at sub-antihypertensive concentrations [41], consistent with the involvement of local cardiac AngII production. Further, our ability to define growth-related roles for AngII using the well characterized ACE inhibitors may be limited, since other enzymes capable of producing AngII from angiotensin I are known to exist abundantly in tissues that are likely targets for locally produced AngII. A leading example is human heart chymase, an enzyme that biochemically shows the potential to be the major AngII-forming enzyme in heart but is not inhibited by the clinically utilized ACE inhibitors [42].

ANGII SIGNALLING MECHANISMS AND GROWTH-RELATED CELLULAR RESPONSES

AngIl-stimulated Second Messenger Pathways

Early biochemical studies of AngII signalling suggested that the cell surface receptor associated with the known physiology of AngII is a member of the family of receptors coupled to phosphoinositide-specific phospholipase C via GTP-binding proteins [4346]. The isolation of cDNAs encoding AngII receptors from rat vascular smooth muscle [47] and bovine adrenal 1481 has provided structural confirmation of this assignment. Activation of this receptor, termed type 1 (ATl), rapidly increases intracellular levels of inositol phosphates, notably inositol 1,4,5-trisphosphate (IP,), and 1,2-diacylglycerol (DAG) in adrenal cortical cells [49], hepatocytes [S&52] and vascular smooth muscle [53,54]. These phosphoinositide-derived second messenger molecules are associated with the mobilization of intracellular calcium stores [55] and the activation of protein kinase C (PKC) isoforms [56], respectively. In addition, AngII has been found to generate DAG by hydrolysis of phosphatidylcholine in hepatocytes [57,58] and smooth muscle cells [59,60]. In accord with the demonstrated intracellular actions of inositol phosphates, Ca2+ and DAGs, AngII has been shown to activate both Ca’+-calmodulin-dependent kinases [61] as well as PKC [62-651. Given that both of these serine/threonine kinase families are well known to play key roles in regulation of the cell cycle and of specific transcriptional events [66,67], it is perhaps not surprising that AngII has a variety of growth-related properties.

Recently, the list of protein kinases activated by AngIl has been extended to include the tyrosine kinase family. By applying anti-phosphotyrosine immunoblotting, immunoprecipitation and phosphoamino acid analysis, we observed rapid AngII-stimulated increases in the phosphotyrosine content of several proteins in WB rat liver epithelial cells [68]. This response was Ca?+-dependent, in that it could be reproduced by the Ca?+ -elevating agents thapsigargin, A23 187 and ionomycin and was blocked in cells loaded with BAPTA a Ca2+ chelator. The response was not mimicked by a PKC-activating phorbol ester, nor was it reduced in PKC-depleted cells. Subsequently, we reported that AngII activates one or more tyrosine kinases, in a manner that is both reflected by and dependent upon the tyrosine phosphorylation


state of the kinases themselves [69]. Other laboratories recently have reported that AngII also is capable of activating tyrosine phosphorylation in vascular smooth muscle cells (VSMC) [70,71] and glomerular mesangial cells [72,73].

Demonstration of Ca*+-dependent, AngII-stimulated tyrosine phosphorylation has been accompanied by a growing awareness that the large family of potentially Ca2+-linked extracellular messengers can influence tyrosine kinases as well as serine/ threonine kinases. Elevation of intracellular Ca?+ appears to be involved in the tyrosine phosphorylation responses to fMet-Leu-Phe [74] and platelet-activating factor [75] in neutrophils, carbachol in CHO cells expressing the m5 muscarinic receptor [76], thrombin in BCHI cells [77] or platelets [78], and NMDA in hippocampal cells [79]. The kinase(s) involved in these novel Ca2+-dependent responses remain to be identified, although, interestingly, negative regulation of the hematopoietic tyrosine kinase ~72~“~ by Cal+ has been reported [80].

Does an intracellular Ca?+ signal regulate growth via tyrosine kinase activation? Although tyrosine kinases are frequently associated with controls of growth and differentiation [81], there is no uniform answer to this question. Admittedly, Ca’+- dependent tyrosine phosphorylation is not always associated with growth, since, as noted above, it occurs in terminally differentiated entities (e.g. platelets and neutrophils) without growth potential. Thus, Ca?+ -dependent tyrosine phosphorylation may have cell-type-dependent functions or even different consequences in a single cell type under various conditions. In WB cells, EGF-stimulated tyrosine phosphorylation occurs in at least two waves [82]. The first wave, occurring within 5 s at 37” or 3s 60 s at o”, appears to be a direct consequence of EGF receptor activation. Within 30 s at 37”, the EGF receptor phosphorylates phosphoinositide-specific phospholipase C-y (PLCy) [83], thereby generating an IP, signal and raising intracellular Ca?‘. This is followed by a second wave of EGF-stimulated tyrosine phosphorylation events, affecting a group of substrates similar to those phosphorylated in response to AngII (Fig. 1). Abrogation of the intracellular Ca?+ signal by chelation with BAPTA, in addition to blocking UN AngII-stimulated tyrosine phosphorylations [68], prevents the second, but not the first, wave of EGF-dependent phosphorylations [68]. The finding of Ca*+-dependent tyrosine phosphorylation stimulated by EGF raises the possibility that these Ca?’ -activated events are responsible in part for growth signalling, at least in some cells.

In some cell types, growth factor receptors with intrinsic tyrosine kinase domains appear to be capable of stimulating cell proliferation in the absence of a Ca?+ signal. This has been demonstrated by several laboratories using receptors modified by site- directed mutagenesis to remove the sites of tyrosine autophosphorylation required for activating PLCy. Receptors for EGF [84], PDGF [85] or FGF [86,87] modified in this fashion were able to transduce a mitogenic signal without eliciting a Ca?+ signal. These findings have prompted the suggestion that Ca*+ mobilization is dispensable for mitogenic signalling by wild-type receptors. Caution must be exercised in interpreting studies of this kind, since they generally ignore the role of CaZ+ derived from PLCy-independent sources [88]. In addition, recent studies by Valius and Kazlauskas [89] demonstrate that the ability of the PDGF receptor to bind and activate PLCyis sufficient to support a mitogenic signal in some cell types. Moreover, it is conceivable that receptor over-expression permits Ca*+-independent elements of growth factor responses to abrogate the need for a Ca*+-dependent component. At physiologic receptor densities and growth factor concentrations, it seems likely that

Control of‘ Growth by Angiotensin II 181

GN4 Cells P-TYR Immunoblot EGF

t iI

t 0% II 37% II I

1 234567 8 9 10 11 12 13 14

EGFR+

p66-7S-) .v P ?

#

FIGURE 1. Tyrosine phosphorylation stimulated by EGF or AngII. Confluent monolayers of GN4 cells (a line derived from the nontransformed WB rat hepatic epithelial cell tine by carcinogen treatment [see 691) were treated at 0 or 37°C with EGF or AngII for the time periods indicated below. Cells were lyzed, run on 10% SDS-polyacrylamide gels, transferred to nitrocellulose and subjected to PT66 (Sigma) P-Tyr immunoblotting as described 168,691. At 0°C EGF stimulated tyrosine pbosphorylation of the EGF receptor (EGFR) and other proteins. At 37°C EGF stimulated the phosphorylation of the same proteins as well as an additional set of substrates in the p66-75 range. This latter group was not phosphorylated at O’C. At 37°C AngII stimulated tyrosine phosphorylation of similar substrates in the p66-75 molecular weight range. Lane 1, O’C-Control; Lanes 24,O”C-EGF, 1 mitt, 5 min, 15 min; Lanes 5-10,37”C-EGF, 15 s, 30 s, 1 mitt, 2 min, 5 min. 15 min; Lanes 1 l-13. 37X-An& 30 s, 45 s, 1 min; Lane 14, 37X-Control.

growth signalling requires multiple pathways acting in concert. It is also reasonable to expect the role of Ca?+ in growth to involve cooperation among diverse extracellular stimuli, as shown for EGF and bradykinin in Swiss 3T3 cells [90].

The so-called mitogen-activated or extracellular signal-regulated protein kinases (MAPKs and ERKs, respectively) have become a focus of interest for many investigators of growth signalling. Recent studies have suggested that these enzymes, in a convergent cascade with MAPK/ERK kinases (MEK), MEK kinases, Raf-1 and protein kinase C, may integrate growth signals from diverse upstream elements, including receptor tyrosine kinase-linked growth factors and G-protein/phospholipase C-linked agents [91-931. Among the targets that are potentially regulated by the MAPKs are the ‘immediate-early growth response’ gene products c-WZJ’C [94] and c-jun [95] (see below). Thus, the activation of MAPKs in response to extracellular stimuli is taken as one indication of the mitogenic potential of these stimuli. In smooth muscle cells, AngII was shown to activate the pp42 and pp44 MAPKs [96,97]. Scott-Burden et al. [98] have reported the activation of a ribosomal S6 kinase by AngII in smooth muscle cells; the Rsk90 form of S6 kinase is another leading candidate for phosphorylation and regulation by the MAPKs [99].

Regulation qf’ Gene Expression b-v Angll

The list of growth-related genes whose expression is influenced by AngII is a long and growing one. AngII induces expression of various immediate-early growth response genes, including efos, ejun, c-~JY, JunB. Egr-I and cMG1, in adrenal


cortical ceils [ lOO,lOl], adrenal medullary cells [ 1021, hepatocytes [ 1031, mesangial cells [104], VSMC [105-1091, heart [l lo], intestinal epithelial cells [I 1 l] and brain [ 1121. Thus, as an activator of PKC, AngII appears capable of regulating gene expression through the AP-1 DNA binding element [113].

In addition to promoting the transcription of early response genes, which themselves function principally as transcriptional regulators, AngII has been found to increase expression of a number of growth factors and their receptors. In WB cells, AngII induced the EGF receptor at both the mRNA and protein levels [ 1141, as well as TGF-cz mRNA [ 1151. In VSMC, AngII was found to increase the density of surface receptors for PDGF [ 1161 and to induce PDPF A-chain [ 117-l 201, basic FGF [121], IGF-1 [ 1221 and heparin-binding EGF-like growth factor [ 123,124]. AngII modulates EGF receptor mRNA levels in rat aorta [125], IGF-1 in adrenal cortical cells [126] and basic FGF in luteal cells [127]. AngII induces preproendothelin-1 mRNA and endothelin- 1 immunoreactivity in cardiac myocytes [128] and endothelin secretion from mesangial cells [129]; endothelin is associated with a host of growth-related actions [ 1301.

AngII is known to influence the expression of other proteins that, although not primary mediators of growth signals, can be viewed as participants in trophic responses. Examples of these include the induction of catecholamine biosynthetic enzymes in adrenal medullary cells [131], 17ar-hydroxylase in adrenal cortical cells [ 1321, and GLUT- 1 glucose transporter in VSMC [ 1331. Components of the extracellular matrix also are candidates for regulation by AngII. Among these are collagens in renal proximal tubular cells [I 341 and VSMC [135] and thrombospondin in smooth muscle [I 361.

Novel AngIl Receptors

As noted above, the known physiologic actions of AngII are mediated by activation of the Ca2+PKC-linked AT1 receptor. Cloning of the AT1 receptor has permitted detailed analysis of its expression and has fueled efforts to clone cDNAs encoding other AngII receptors/binding proteins whose functions are more enigmatic [137-1401. The most widely studied of these other putative receptors is the AT2 binding site, which was biochemically distinguished from the AT1 receptor by Gunther [ 1411 based on its resistance to sulfhydryl reducing agents. Subsequently, the development of site-selective receptor ligands has defined the AT2 site pharmacologi- cally [142-1451. In the absence of well characterized immunologic or genetic probes, site-selective ligands have been used to identify tissues and cell lines that express the AT2 site. By using in situ receptor binding followed by autoradiography, several investigators have noted that AT2 binding occurs at relatively high levels in perinatal rat aorta [146] and brain [147-1491, while expression in the adult is less common.

Occupancy of the AT2 site with AngII does not elicit the spectrum of responses associated with the AT1 site [150-1531. Although there have been several reports linking the AT2 site with such diverse responses as plasma membrane Ca2+ flux [154], inhibition of phosphoinositide hydrolysis [ 1551, elevation of tyrosine phosphatase activity [156], reduction in blood pressure [157,158], and prostaglandin synthesis [159], there is no well accepted model of AT2 signalling or physiology. Nonetheless, the marked post-natal decline in AT2 expression have suggested a role for this site during fetal development. Moreover, in adult animals, the AT2 site has been

Control of Growth by Angiotensin II

AT,-mediated Stimulation of WB Cell Proliferation

Control Saralasin Losattan PD123177

FIGURE 2. Stimulation of WB cell proliferation by AagII. Subconfluent, adherent cultures of WB cells were treated for 6 days in serum-free Richter’s improved medium (supplemented with insulin, transferrin and selenium) alone or supplemented medium containing 50 rig/ml EGF or 10 nM A&I. The AngIl receptor antagonists Saralasin fSa+Ala~AngII), Losartan or PDl23177 were added (1 w) at the time of EGF or AngIl addition. Cell numbers were determined using a Coulter Counter and are expressed (mean f sem, D= 3 determinations) as a percentage of the number accumulating in tbe presence of 10% fetal bovine serum.

implicated in responses to vascular injury, in that subtype-selective AT2 antagonists inhibit neointimal formation following experimental balloon angioplasty [160,161]. Newly described anti-AT2 antisera [ 1621, as well as the recent cDNA cloning of AT2 sites [162a,b], should provide the requisite tools for delineating AT2 function.

The identification of the mas oncogene as an angiotensin II receptor actually predated the cloning of the AT1 receptor by some 3 years [163]. The maslAng receptor apparently can mediate phosphoinositide hydrolysis and Ca2+ mobilization in response to AngTI [164]. However, the unique pharmacologic profile of this receptor, including its greater responsiveness to angiotensin III, render its relationship to the other known and putative AngII receptors uncertain. Ongoing investi- gations into the distribution and function of the mas proto-oncogene and its relatives, particularly in neural tissue. will likely clarify this intriguing issue [ 165,167].

IS ANGII A MITOGEN?

The definition of a mitogen is straightforward: a substance that increases the rate of cell division. Thus there is no question that, under appropriate conditions, AngII can act as a mitogen. This was documented in early studies using adrenocortical cells [S] and more recently has been demonstrated to occur via recombinant AT1 receptors expressed in CHO cells [168]. In our own studies, AngII treatment of WB cells in a defined serum-free medium approximately doubled cell number over a 6-day period (Fig. 2); this response was selectively inhibited by the AT1 receptor antagonist Losartan.

However, for AngII and other vasoactive agents with similar growth-promoting

184 W. R. Huckk and H. S. Earp

activities (e.g. vasopressin and endothelin), acceptance as mitogens, particularly in vascular smooth muscle, is not afuit accompli [169-1711. One reason for this is the technical limitation of popular procedures for estimating a cell proliferation response. In numerous reports, relatively modest increases in [3H]thymidine incorporation by cells treated with Angii are taken as sole evidence of a mitogenic response, although it is recognized that this type of analysis alone does not always correlate with DNA replication [ 1721. Nevertheless, AngII has met the more rigorous mitogenic standard of increasing cell number in a variety of cell culture systems, including renal arteriolar smooth muscle cells [173] and rodent [134,174] and human glomerular mesangial cells [ 1751.

Interest in the growth-promoting activities of AngII toward vascular smooth muscle stems largely from the potential role of AngII in vascular hypertrophy or hyperplasia associated with hypertension and atherogenesis [ 176,177]. Several laboratories have reported that AngII acts on normotensive rat aortic smooth muscle cells principally as a hypertrophic agent [178,179]. This response is characterized by increases in cell size and protein content but not by increased cell number or marked DNA synthesis. In contrast, other investigators, using aortic [18&l 821 or mesenteric arterial smooth muscle cells [183] derived from spontaneously hypertensive rats, have demonstrated increased cell proliferation in response to AngII. The availability of these differentially-responsive cellular models has presented an opportunity to identify factors that influence the mitogenic potential of AngII.

One concept that has emerged from recent studies is that the net response of VSMC to AngII is determined by the balance between secondary, AngII-induced proliferative and anti-proliferative signals. Specifically, Hahn et al. [ 1181 have reported that, in addition to PDGF-A induction, AngII simultaneously induces expression of TGF-/I, a factor associated with both positive and negative growth responses [184]. Autocrine PDGF-AA is postulated to mediate at least part of the hypertrophic effect of AngII [ 1171, while AngII-induced basic FGF has been implicated as an ‘ultimate’ smooth muscle mitogen [121]. However, the ability of basic FGF, PDGF or other mitogens to successfully stimulate cell division in VSMC may be modulated by ambient or induced levels of TGF-/I [185-l 871. Blockade of autocrine TGF-j3 action by exposure to neutralizing antibodies against TGF-p allows AngII to become an outright mitogen in VSMC from normotensive rats, suggesting that TGF-I) otherwise serves to dampen the potentially mitogenic signal from AngII [188]. More recently, Koibuchi et al. [189] have described several normotensive VSMC culture preparations that vary in their mitogenic responses to AngII according to their abilities to generate active TGF-P from the latent, secreted form [190].

Interestingly, the addition of neutralizing anti-TGF-pantibodies has quite different effects on VSMC derived from spontaneously hypertensive rats. In these cultures, active TGF-/I also is inducible by AngII, but its autocrine action appears to be mitogenic rather than anti-proliferative [ 1911. Thus, these findings offer a framework for understanding the differential responsiveness of normotensive and spontaneously hypertensive rat-derived VSMC cultures to AngII. It is likely that recent advances in the study of TGF-/I binding proteins [ 1921, receptor distribution, signal transduction [193] and cell cycle regulation [I941 will help clarify the complex roles of this growth factor in AngII action.

In addition to its postulated roles in atherogenesis and hypertension, AngII is a potential mediator of the response of vascular muscle to acute trauma [195]. AngII

C’ontrol of Growth by Angiotensin II ix.5

can potentiate neointimal VSMC proliferation in experimental models of injury [196]. and there is evidence that AT1 receptor expression [197] and local production of AngII [ 198,199] and TGF-P [200] may be enhanced following injury. Although ACE inhibitors effectively inhibit vascular restenosis following experimental angioplasty in rats [301-2041, similar observations have not been made in porcine [205,206] or primate [207] models or in human trials [208]. It should be noted, however, that different enzymatic mechanisms of angiotensin I conversion may predominate in rat and human tissues [209,210]. AngII receptor antagonists, which block AngII action irrespective of its mode of production, are also effective inhibitors of neointimal formation in animal models of vascular injury [160,21 l-2141. It is anticipated that experimentai and, perhaps, clinical experience with these potent and selective antagonists will eventually provide, as have the ACE inhibitors in hypertension, a body of data sufficient to define the roles of AngII in vascular growth regulation.

PROSPECTS

In many respects, the major unresolved issues concerning AngII signalling are the same as those encountered in the study of any potentially mitogenic compound. These include the thorough elucidation of kinase cascades linking receptor occupancy to the nuclear events controlling transit through the cell cycle. The recent advances in characterization of the mammalian cyclin-dependent kinases [215,216], as well as the developments in MAP kinase pathways discussed above, promise to provide new insights into this linkage. For AngII, we also must define the extent and nature of the integration between Ca2+/PKC-dependent pathways and those initiated by the receptor tyrosine kinases. This need applies especially to our efforts to understand the effects of AngII in the simultaneous presence of a multitude of other growth stimulators and inhibitors.

REFERENCES

1. Elliott DF. Peart WS. Amino acid sequence of a hypertensin. Nature 1956; 177: 527-528. 2. Skeggs LT, Lentz KE, Kahn JR. Shumway NP, Woods KR. The amino acid sequence of

hypertensin II. J Exp Med. 1956; 104: 193-197. 3. Skeggs LT. Discovery of the two angiotensin peptides and the angiotensin converting enzyme.

Hypertension 1993; 21: 259-260. 4. Robertson JIS. Nicholls MC, eds. The renin-ungiotensin system. Vols 1 and 2. Cower Medical

Publishing, London; 1993. 5. Gil GN, Ill CR, Simonian MH. Angiotensin stimulation of bovine adrenocortical cell growth. Proc

Nat/ Acad Sri USA. 1977; 74: 5569-5573. 6. Schelling P, Ganten D, Speck G, Fischer H. Effects of angiotensin II and angiotensin II antagonist

saralasin on cell growth and renin in 3T3 and SV3T3 cells. J Cell Physiol. 1979; 98: 503-514. 7. Campbell JH, Tachas G, Black MJ, Cockerill G, Campbell CR. Molecular biology of vascular

hypertrophy. Basic Res Curdiol. 1991; 1: 3-l 1. 8. Casscells W. Smooth muscle cell growth factors. Prog Growth Factor Res. 1991; 3: 177-206. 9. Clauser E, Bihoreau C. Monnot C, Teutsch B, Conchon S, Davies E, Corvol P. Is angiotensin II a

growth factor? Diabete Metab. 1992; 18: 129-136. 10. Hanley MR. Neuropeptides as mitogens. Nature 1985; 315: 14-15. I 1. Heagerty BM. Angiotensin II: vasoconstrictor or growth factor? J Cardiovasc Pharmacol. 1991; 18

(suppl. 2): Sl4-s19. 12. Katz AM. Angiotensin II: hemodynamic regulator or growth factor? J Mel Cell Cardiol. 1990; 22:

739-747.


13.

14. 15.

16.

17.

18.

19.

20. 21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

Naftilan AJ. The role of angiotensin II in vascular smooth muscle cell growth. J Cardiovasc Pharmacol. 1992; 20 (suppl. I): S37-S40. Norman JT. The role of angiotensin II in renal growth. Renal Physiol Biochem. 1991; 14: 175-185. Owens GK. Role of contractile agonists in growth regulation of vascular smooth muscle cells. Adv Exp Med Biol. 1991; 308: 71-79. Re R. Angiotensin and the regulation of cellular growth. Pathophysiologic implications for cardiovascular and noncardiovascular tissues. Am J Hypertens. 199 I; 4: 2 17%2 19% Schelling P, Fischer H, Ganten D. Angiotensin and cell growth: a link to cardiovascular hypertrophy? J Hypertens. 1991; 9: 3-15. Scott-Burden T, Hahn AW, Buhler FR, Resink TJ. Vasoactive peptides and growth factors in the pathophysiology of hypertension. J Cardiovasc Pharmacol. 1992; 20 (suppl. I): S55-S64. Zachary I, Woll PJ, Rozengurt E. A role for neuropeptides in the control of cell proliferation. Dev Biol. 1987; 124: 295-308. Johnson CI. Biochemistry and pharmacology of the renin-angiotensin system. Drugs 1990; 1: 21-31. van Sande M, Scharpe SL, Neels HM, van Camp KO. Distribution of angiotensin converting enzyme in human tissues. Clin Chim Acta 1985; 147: 2555260. Frohlich ED, Iwata T, Sasaki 0. Clinical and physiologic significance of local tissue renin- angiotensin systems. Am J Med. 1989; 87 (suppl. 6B): 19%23s. Johnston CI, Burrell LM. Perich R. Jandeleit K, Jackson B. The tissue renin-angiotensin system and its functional role. Clin Exp Pharmacol Physiol Suppl. 1992; 19: l-5. Griendling KK. Murphy TJ, Alexander RW. Molecular biology of the renin-angiotensin system. Circulufion 1993; 87: 18161828. Baker KM, Booz GW. Dostal DE. Cardiac actions of angiotensin II: Role of an intracardiac renin- angiotensin system. Annu Rev Physiol. 1992; 54: 227-241. Dzau VJ. Cardiac renin-angiotensin system. Molecular and functional aspects. Am J Med. 1988; 84: 22-27. Grinstead WC, Young JB. The myocardial renin-angiotensin system: existence, importance. and clinical implications. Am Heart J. 1992; 123: 1039-1045. Mebazaa A. Chevalier B. Mercadier JJ, Echter E, Rappaport L, Swynghedauw B. A review of the renin-angiotensin system in the normal heart. J Curdiovusc Pharmacol. 1989; 14 (suppl. 4): Sl&S20. Iwai N. Matsunaga M, Kita T, Tei M, Kawai C. Regulation of renin-like enzyme in cultured human vascular smooth muscle cells. Jpn Circ J. 1988; 52: 1338-1345. Morishita R, Higaki J, Miyazaki M. Ogihara T. Possible role of the vascular renin-angiotensin system in hypertension and vascular hypertrophy. H.vpertension 1992: 19 (suppl. 2): 1162-1167. Bunnemann B. Fuxe K, Ganten D. The brain renin-angiotensin system: localization and general significance. J Curdiovasc Pharmacol. 1992: 19 (suppl. 6): S51-S62. Burns KD, Homma T, Harris RC. The intrarenal renin angiotensin system. Semin Nephrol. 1993; 13: 13.-30. Sarzani R, Fallo F. Dessi FP, Pistorello M, Lanari A, Paci VM, Mantero F, Rappelli A. Local renin--angiotensin system in human adrenals and aldosteronomas. Hyperfension 1992; 19: 702-707. Asmar RG. Pannier B. Santoni JP. Laurent S. London GM, Levy BI, Safar ME. Reversion of cardiac hypertrophy and reduced arterial compliance after converting enzyme inhibition in essential hypertension. Circulation 1988; 78: 941-950. Gilbert BW. ACE inhibitors and regression of left ventricular hypertrophy. Clin Cardiol. 1992: 15: 711 714. Gohlke P, Stall M, Lamberty V, Mattfeld T, Mall G. van Even P, Martorana P, Unger T. Cardiac and vascular effects of chronic angiotensin converting enzyme inhibition at subantihypertensive doses. J Hypertens Suppl. 1992; 10: S141-S144. Kloner RA. Przyklenk K. Cardioprotection with angiotensin-converting enzyme inhibitors: rede- fined for the 1990s. Clin Cardiol. 1993; 16: 95-103. Massie BM. Angiotensin-coverting enzyme inhibitors as cardioprotective agents. Am J Cardiol. 1992; 70: 101-171. Paul M, Ganten D. The molecular basis of cardiovascular hypertrophy: the role of the renin- angiotensin system. J Cardiovusc Pharmacol. 1992: 19 (suppl. 5): S51-S58. Farhy RD. Ho KL, Carretero OA. Scicli AC. Kinins mediate the antiproliferative effect of ramipril in rat carotid artery. Biochem Biophys Res Commun. 1992; 182: 283-288. Owens GK. Differential effects of antihypertensive therapy on vascular smooth muscle cell

Control y f Growth by Angiotensin If IN?

42.

43.

44.

45.

46, 47.

48.

49.

50.

51.

52.

53.

54.

55. 56.

57.

58.

59.

60.

61.

62.

63.

hypertrophy, hyperploidy, and hyperplasia in the spontaneously hypertensive rat. Circ Re.y. 1985: 56: X2-536. Urata H, Kinoshita A, Misono KS. Bumpus FM, Husain A. Identification of a highly specific chymase as the major angiotensin II-forming enzyme in the human heart. J Biol Chem. 1990; 265. 22348822357. Bouscarel B. Blackmore PF. Exton JH. Characterization of the angiotensin II receptor in primary cultures of rat hepatocytes. evidence that a single receptor is coupled to two different responses. J Biol Chem. 1988; 263: 14913-14919. (‘rane JK, Campanile CP, Garrison JC. The hepatic angiotensin II receptor, effect of guanine nucleotides and interaction with cyclic AMP production. J Biol Chem. 1982; 257: 4959.~4965. Fain JN, Wallace MA. Wojcikiewicz RJH. Evidence for involvement of guanine nucleotide-binding regulatory proteins in the activation of phospholipases by hormones. FASEB J. 1988; 2: 2569- 2574. Martin TFJ. Receptor regulation of phosphoinositidase C. Phurmucol Ther. 1Y91; 49: 329-345. Murphy TJ. Alexander RW, Griendling KK. Runge MS, Bernstein KE. Isolation of a cDNA encoding the vascular type-l angiotensin II receptor. Nurure I99 I: 351: 2333236. Sasaki K. Yamano Y, Bardhan S. Iwai N. Murray JJ, Hasegawa M. Matsuda Y, lnagami T. Cloning and expression of a complimentary DNA encoding a bovine adrenal angiotensin 11 type- I receptor. Nature 1991; 351: 230-233. Kojima I. Kojima K. Kreutter D, Rasmussen H. The temporal integration of the aldosterone secretory response to angiotensin occurs via two intracellular pathways. J Biol Chem. 1984: 259: 14448-14457. Bocckino SB, Blackmore PF, Exton JH. Stimulation of I .2-diacylglycerol accumulation in hepatocytes by vasopressin, epinephrine, and angiotensin II. J Biol Chem. 1985; 260: 14201-14207. (‘harest R. Prpic V. Exton JH, Blackmore PF. Stimulation of inositol trisphosphate formation in hepatocytes by vasopressin, adrenaline and angiotensin II and its relationship to changes in cytosolic lice Ca? Biorhem J. 1985: 227: 79-90. Williamson JR, Cooper RH, Joseph SK, Thomas AP. Inositol trisphosphate and diacylglycerol as intracellular second messengers in liver. Am J Physiol. 1985; 248: C203--C216. Smith JB, Smith L, Brown ER, Barnes D, Sabir MA, Davis JS. Farese RV. Angiotensin II rapidly increases phosphatidate-phosphoinositide synthesis and phosphoinositide hydrolysis and mobilizes intracellular calcium in cultured arterial muscle cells. Proc Nut/ Acud Sci USA. 1984; 8 1: 78 l2- 78 16. Alexander RW. Brock TA, Gimbrone MA, Rittenhouse SE. Angiotensin increases inositol triphosphate and calcium in vascular smooth muscle. Hypertension 1985: 7: 447-451. Berridge MJ. Inositol trisphosphate and calcium signalling. Nature 1993; 361: 3 15-325. Nishizuka Y. Intracellular signaling by hydrolysis of phospholipids and activation of protein kinase C‘. S?ience 1992; 258: 607614. Augert G. Bocckino SB. Blackmore PF, Exton JH. Hormonal stimulation of diacylglycerol formation in hepatocytes. Evidence for phosphatidylcholine breakdown. J Biol Chem. 1989; 264. 21689 71698. Pittner RA, Fain JN. Activation of membrane protein kinase C by glucagon and Ca(2+)-mobilizing hormones in cultured rat hepatocytes. Role of phosphatidylinositol and phosphatidylcholine hydrolysis. Bidrem J. 1991; 277: 371-378. Kondo T. Konishi F, Inui H, Inagami T. Diacylglycerol formation from phosphatidylcholine in angiotensin II-stimulated vascular smooth muscle cells Biochem Biophys Rr.s Commun. 1992; 187. 1460 1465. Lassegue B, Alexander RW. Clark M, Griendling KK. Angiotensin II-induced phosphatidylcholine hydrolysis in cultured vascular smooth-muscle cells. Regulation and localization. Biochem J. 1991: ‘76: 19 25. (‘onnelly PA. Sisk RB. Schulman H. Garrison JC. Evidence for the activation of the multifunctional (‘a’ ;calmodulin-dependent protein kinase in response to hormones that increase intracellular Ca: J Biol Chem. 1987: 262: 1015410163. Garrison JC. Johnsen DE, Campanile CP. Evidence for the role of phosphorylase kinase. protein kinase C. and other Ca’+-sensitive protein kinases in the response of hepatocytes to angiotensin II and vasopressin. J Biol Chem. 1984: 259: 3283-3292. Lang U, Vallotton MB. Effects of angiotensin II and of phorbol ester on protein kinase C activity and on prostacyclin production in cultured rat aortic smooth-muscle cells. Blochem J. 1989: 259: 477483.

188 W. R. Huckle and H. S. Ear-p

64.

65.

66.

67.

68.

69.

70.

71.

12.

73.

74.

15.

76.

II.

78.

79.

80.

81.

82.

83.

84.

85.

86.

81. Mohammadi M. Dionne CA. Li W. Li N, Spivak T, Honegger AM, Jaye M, Schlessinger J. Point

Tang EK. Houslay MD. Glucagon, vasopressin and angiotensin all elicit a rapid. transient increase in hepatocyte protein kinase C activity. &o&m J. 1992; 283: 341 -346. Tuominen RK, Hudson PM, McMillian MK, Ye H. Stachowiak MK. Hong JS. Long-term activation of protein kinase C by angiotensin II in cultured bovine adrenal medullary cells. J Neurochem. 1991; 56: 1292.1298. Karin M, Smeal T. Control of transcription factors by signal transduction pathways: the beginning of the end. Trends Biochem Sri. 1992; 11: 418422. Lu KP. Means AR. Regulation of the cell cycle by calcium and calmodulin. Endo Rev. 1993: 14: 40-58. Huckle WR, Prokop CA, Dy RC, Herman B, Earp S. Angiotensin II stimulates protein-tyrosine phosphorylation in a calcium-dependent manner. Mel Cell Biol. 1990b; IO: 6290-6298. Huckle WR. Dy RC, Earp HS. Calcium-dependent increase in tyrosine kinase activity stimulated by angiotensin II. Proc Nat1 Acad Sri USA. 1992; 89: 8837-8841. Molloy CJ, Taylor DS, Weber H. Angiotensin II stimulation of rapid protein tyrosine phosphorylation and protein kinase activation in rat aortic smooth muscle cells. J Biol Chem. 1993: 268: 7338 1345. Tsuda T, Kawahara Y, Ishida Y, Koide M, Shii K. Yokoyama M. Angiotensin 11 stimulates two myehn basic protein/microtubule-associated protein 2 kinases in cultured vascular smooth muscle cells. Circ Res. 1992; 11: 620-630. Force T. Kyriakis JM. Avruch J. Bonventre JV. Endothehn, vasopressin. and angiotensin 11 enhance tyrosine phosphorylation by protein kinase C-dependent and -independent pathways in glomerular mesangial cells. J Biol Chem. 1991; 266: 6650-6656. Salles J-P, Gayral-Taminh M, Fauvel J, Delobbe I, Mignon-Conte M, Conte JJ. Chap H. Sustained effect of angiotensin II on tyrosine phosphorylation of annexin I in glomerular mesangial cells. J Biol Chem. 1993; 268: 12805512811. Huang C-K, Bonak V, Laramee CR, Casnellie JE. Protein tyrosine phosphorylation in rabbit peritoneal neutrophils. Biochem J. 1990; 269: 431436. Gomez-Cambronero J. Wang E. Johnson G, Huang C-K, Sha’afi RI. Platelet-activating factor induces tyrosine phosphorylation in human neutrophils. J Biol Chem. 1991; 266: 624&6245. Gusovsky F, Luedens JE, Kohn EC, Felder CC. Muscarinic receptor-mediated tyrosine phosphorylation of phospholipase C-y. J Biol Chem. 1993; 268: 7768S7712. Offermanns S, Bombien E. Schultz G. Thrombin Ca?l-dependently stimulates protein tyrosine phosphorylation in BC3HI cells Biochem J. 1993; 290: 27 32. Vostal JG, Jackson WL. Shulman NR. Cytosolic and stored calcium antagonistically control tyrosine phosphorylation of specific platelet proteins. ./ Biol Chem. 1991: 266: 1691 I- 16916. Bading H. Greenberg ME. Stimulation of protein tyrosine phosphorylation by NMDA receptor. Science 1991; 253: 912-914. Taniguchi T, Kitagawa H, Yasue S, Yanagi S. Sakai K. Asahi M. Ohta S, Takeuchi F. Nakamura S, Yamamura H. Protein-tyrosine kinase p72 rlk is activated by thrombin and is negatively regulated through Ca*+ mobilization in platelets. J Biol Chem. 1993; 268: 2277-2279. Ullrich A, Schlessinger J. Signal transduction by receptors with tyrosine kinase activity. Cell 1990: 61: 203 -212. McCune BK, Earp HS. The epidermal growth factor receptor tyrosine kinase in liver epithelial cells. J Biol Chem. 1989; 264: 15501~15507. Huckle WR, Hepler JR, Rhee SC. Harden TK. Earp HS. Protein kinase C inhibits epidermal growth factor-dependent tyrosine phosphorylation of phospholipase C-y and activation of phosphoinositide hydrolysis. Endocrinology 1990; 121: 169771705. Chen WS. Lazar CS, Lund KA, Welsh JB, Chang CP, Walton GM, Der CJ, Wiley HS. Gill GN. Rosenfeld MC. Functional independence of the epidermal growth factor receptor from a domain required for ligand-induced internalization and calcium regulation. Cell 1989; 59: 3343. Ronnstrand L, Mori S, Arridsson A-K. Eriksson A, Wernstedt C. Hellman U, Claesson-Welsh L. Heldin C-H. Identification of two C-terminal autophosphorylation sites in the PDGF preceptor: involvement in the interaction with phospholipase C-y. EMBO J. 1992; 1 I: 391 l-3919. Peters KG, Marie J. Wilson E. Ives HE. Escobedo J, Del Rosario M, Mirda D, Williams LT. Point mutation of an FGF receptor abolishes phosphatidylinositol turnover and Cal’ flux but not mitogenesis. Nafure 1992; 358: 6788681.

Control of’ Growth by Angiotensin II 1X9

X8.

x9.

90.

‘)I.

9.

Y3.

Y4.

Y5.

96.

Yl.

YX.

99.

100.

101.

102.

103.

104.

105.

106.

107.

108.

mutation in FGF receptor eliminates phosphatidylinositol hydrolysis without affecting mitogencsls. ,Vature 1992; 358: 681-684. Magni M. Meldolesi J, Pandiella A. Ionic events induced by epidermal growth factor. evidence that hyperpolarization and stimulated calcium influx play a role in the stimulation of cell growth. J Biol (‘hem. 1991; 266: 6329 -6335. Valius M, Kazlauskas A. Phospholipase C-yl and phosphatidylinositol 3 kinase are downstream mediators of the PDGF receptor’s mitogenic signal. Cell 1993: 73: 321.-334. Olsen R, Santone K, Melder D. Oakes SC. Abraham R, Powis G. An increase in intracellular free ( ‘a2 ’ associated with serum-free growth stimulation of Swiss 3T3 fibroblasts by epidermal growth factor in the presence of bradykinin. J Biol Chem. 1988; 263: 18038%18035. (‘ha0 T-SO. Byron KL, Lee K-M, Villereal M, Rosner MR. Activation of MAP kinases by calcium- dependent and calcium independent pathways, stimulation by thapsigargin and epidermal growth I;lctor. J Biol Chem. 1992; 267: 1987&19883. Kolch W, Heidecker G. Kochs G. Hummel R, Vahidi H, Mischak H, Finkenzeller G, Marme D. Rapp UR. Protein kinase Ca activates RAF-l by direct phosphorylation. Nature 1993: 364: 249- 252.

Lange-Carter CA, Pleiman CM, Gardner AM, Blumer KJ. Johnson CL. A divergence in the MAP kinase regulatory network defined by MEK kinase and Raf. Science 1993; 260: 315-319. Seth A. Alvarez E, Gupta S, Davis RJ. A phosphorylation site located in the NhZ-terminal domain ofc-n~~~c increases transactivation of gene expression. J Biol Chem. 1991: 266: 23521-23524. Baker SJ, Kerppola TK, Luk D, Vandenberg MT, Marshak DR. Curran T. Jun is phosphorylated by several protein kinases at the same sites that are modified in serum-stimulated fibroblasts. Mel CLII Biol. 1992; 12: 4694-4105. Duff JL, Berk BC, Corson MA. Angiotensin II stimulates the pp44 and pp42 mitogen-activated protein kinases in cultured rat aortic smooth muscle cells. Biochem Biophys Res Commun. 1992: 188: 257 264. Tsuda T, Kawahara Y. Shii K, Koide M, Ishida Y, Yokoyama M. Vasoconstrictor-induced protein- t) rosine phosphorylation in cultured vascular smooth muscle cells. FEES Lett. 1991; 285: 44 48. Scott-Burden T, Resink TJ, Baur U, Burgin M, Buhler FR. Amiloride sensitive activation of S6 klnase by angiotensin II in cultured vascular smooth muscle cells. Biochem Bioph.w Res Commurz. lY88: 151: 583+589. C hung J, Pelech SL. Blenis J. Mitogen-activated Swiss mouse 3T3 RSK kinases 1 and 11 are related to pp44mpk from sea star oocytes and participate in the regulation of pp90rsk activity. Proc, Nurl .Jcad Sci USA. 1991: 88: 49814985. Clark AJ, Balla T. Jones MR, Catt KJ. Stimulation of early gene expression by angiotensin I1 in bovine adrenal glomerulosa cells: roles of calcium and protein kinase C. Mel Etzdocrinol. 1992; 6: I X89- 1898. Viard I. Hall SH, Jaillard C, Berthelon MC, Saez JM. Regulation ofc:fos, c-jun andjun-B messenger rihonucleic acids by angiotensin-II and corticotropin in ovine and bovine adrenocortical cells. Dldocrinology 1992; 130: 193-200. Stachowiak MK. Sar M. Tuominen RK, Jiang HK, An S, Iadarola MJ, Poisner AM, Hong JS. Stimulation of adrenal medullary cells in viva and in vitro induces expression of c+s proto- oncogene. Oncogene 1990b; 5: 69-573. Gonzalez EC, Garcia SJ. Angiotensin II and active phorbol esters induce proto-oncogene expression in isolated rat hepatocytes. Biochim Biophys Acta. 1992; I 136: 309-314. Rupprecht HD, Dann P. Sukhatme VP. Sterzel RB, Coleman DL. Effect of vasoactive agents on induction of Egr-I in rat mesangial cells: correlation with mitogenicity. Am .I Phvsiol. 1992; 263: Fh23-~F636. Kawahara Y, Sunako M, Tsuda T, Fukuzaki H. Fukumoto Y. Takai Y. Angiotensin II induces expression of the c:fi)s gene through protein kinase C activation and calcium ion mobilization in cultured vascular smooth muscle cells. Biochem Biophys Res Commun. 1988; 150: 52-59. Nnftilan AJ. Gilliland GK. Eldridge CS. Kraft AS. Induction of the proto-oncogene c-jun by angiotensin II. Mel Cell Biol. 1990; IO: 5536-5540. Naftilan AJ, Pratt RE, Edlridge CS. Lin HL, Dzau VJ. Angiotensin II induces c:fos expression in smooth muscle via transcriptional control. Hypertension 1989; 13: 706-711. Sachinidis A, Weisser P, Ko Y. Schulte K, Meyer zBK, Neyses L. Vetter H. Angiotensin 11 induces

I90 W. R. Huckle and H. S. Earp

109.

110.

111.

112.

113.

114.

115.

116.

117.

118.

119.

120.

121.

122.

Itoh H, Mukoyama M. Pratt RE. Gibbons GH. Dzau VJ. Multiple autocrine growth factors modulate vascular smooth cell growth response to angiotensin II. J Clin Invest. 1993; 91: 2268-2274. Delafontaine P. Lou H. Angiotensin II regulates insulin-like growth factor I gene expression in vascular smooth muscle cells. / Biol Chem. 1993; 268: 1686616870.

123. Temizer DH, Yoshizumi M, Perrella MA. Susanni EE, Quertermous T. Lee ME. Induction of heparin-binding epidermal growth factor-like growth factor mRNA by phorbol ester and angiotensin II in rat aortic smooth muscle cells. J Biol Chem. 1992; 267: 24892-24896.

124.

125.

Dluz SM, Higashiyama S. Damm D, Abraham JA, Klagsbrun M. Heparin-binding epidermal growth factor-like growth factor expression in cultured fetal human vascular smooth muscle cells, induction of mRNA levels and secretion of active mitogen. J Biol Chem. 1993; 268: 18330-18334. Sambhi MP. Swaminathan N, Wang H, Rong H. Increased EGF binding and EGFR mRNA expression in rat aorta with chronic administration of pressor angiotensin II. Biochem Med Metah Bid. 1992; 48: 8-18.

126. Penhoat A, Leduque P, Jaillard C, Chatelain PG, Dubois PM. Saez JM. ACTH and angiotensin II regulation of insulin-like growth factor-I and its binding proteins in cultured bovine adrenal cells. J Mel Endocrinol. 1991: 7: 223-232.

127. Stirling D, Magness RR. Stone R. Waterman MR. Simpson ER. Angiotensin II inhibits luteinizing

formation of the early growth response gene-l protein in rat vascular smooth muscle cells. FEES Left. 1992; 313: 1099112. Taubman MB, Berk BC, Izumo S, Tsuda T. Alexander RW, Nadal GB. Angiotensin II induces c-fo.s mRNA in aortic smooth muscle. Role of Ca2’ mobilization and protein kinase C activation, J Biol Chem. 1989; 264: 526530. Moalic JM, Bauters C. Himbert D, Bercovici J, Mouas C, Guicheney P, Baudoin LM, Rappaport L, Emanoil RR, Mezger V. et al. Phenylephrine, vasopressin and angiotensin II as determinants of proto-oncogene and heat-shock protein gene expression in adult rat heart and aorta. J H~pertens. 1989; 7: 1955201. Gomperts M, Corps AN, Pascal JC, Brown KD. Mitogen-induced expression of the primary response gene cMG1 in a rat intestinal epithelial cell-line (RIE-1). FEBS Leff. 1992; 306: l-4. McKinley MJ. Badoer E, Oldgeld BJ. Intravenous angiotensin II induces Fos-immunoreactivity in circumventricular organs of the lamina terminalis. Brain Res. 1992; 594: 295-300. Takeuchi K, Nakamura N, Cook NS. Pratt RE. Dzau VJ. Angiotensin II can regulate gene expression by the AP-1 binding sequence via a protein kinase C-dependent pathway. Biochem Biophys Res Commun. 1990; 172: 1189-l 194.

Earp HS, Hepler JR, Petch LA, Miller A, Berry AR. Harris J, Raymond VW, McCune BK, Lee LW, Grisham JW, et al. Epidermal growth factor (EGF) and hormones stimulate phosphoinositide hydrolysis and increase EGF receptor protein synthesis and mRNA levels in rat liver epithelial cells. Evidence for protein kinase C-dependent and -independent pathways. J Biol Chem. 1988; 263: 13868813874. Raymond VW, Lee DC, Grisham JW, Earp HS. Regulation of transforming growth factor alpha messenger RNA expression in a chemically transformed rat hepatic epithelial cell line by phorbol

ester and hormones. Cancer Res. 1989; 49: 3608-3612. Bobik A, Grinpukel S, Little PJ, Grooms A, Jackman G. Angiotensin II and noradrenaline increase PDGF-BB receptors and potentiate PDGF-BB stimulated DNA synthesis in vascular smooth muscle. Biochem Biophys Res Commun. 1990; 166: 58&588. Berk BC, Rao GN. Angiotensin H-induced vascular smooth muscle cell hypertrophy: PDGF A- chain mediates the increase in cell size. J Cell Ph.vsiol. 1993; 154: 3688380. Hahn AW, Resink TJ. Bernhardt J, Ferracin F, Buhler FR. Stimulation of autocrine platelet- derived growth factor AA-homodimer and transforming growth factor beta in vascular smooth

muscle cells. Biochem Eiophw Res Commun. 1991; 178: 1451-1458. Naftilan AJ, Pratt RI!, Dzau VJ. Induction of platelet-derived growth factor A-chain and c-myc gene expressions by angiotensin II in cultured rat vascular smooth muscle cells. J C/in Invest. 1989a; 83: 1419-1424. Nakahara K, Nishimura H, Kuroo M. Takewaki S, Iwase M. Ohkubo A, Yazaki Y, Nagai R. Identification of three types of PDGF-A chain gene transcripts in rabbit vascular smooth muscle and their regulated expression during development and by angiotensin II. Biochem Biophys Res Commun. 1992; 184: 81 l-818.

Cbntrof of Growth 6-v Angiotensin I/ IYI

128.

129.

130.

131.

132.

133.

134.

135.

136.

137.

138.

139.

140.

141.

142.

143.

144.

145.

146.

147.

148.

149.

150.

151.

hormone-stimulated cholestrol side chain cleavage expression and stimulates basic fibroblast growth factor expression in bovine luteal cells in primary culture. J Biol Chem. 1990; 265: 5-8. Ito H, Hirata Y, Adachi S, Tanaka M, Tsujino M, Koike A, Nogami A, Marumo F. Hiroe M. Endothelin-l is an autocrine/paracrine factor in the mechanism of angiotensin II-induced hypertrophy in cultured rat cardiomyocytes. J Clin Invest. 1993; 92: 39843. Kohno M, Horio T, Ikeda M. Yokokawa K, Fukui T, Yasunari K. Kurihara N, Takeda T. Angiotensin II stimulates endothelin-I secretion in cultured rat mesangial cells. Kidnqv Int. 1992; 42: X60-836. Battistini B, Chailler P, D’Orleans-Juste P, Briere N, Sirois P. Growth regulatory properties of endothelins. Peptides 1993; 14: 3855399. Stachowiak MK. Jiang HK, Poisner AM. Tuominen RK. Hong JS. Short and long term regulation of catecholamine biosynthetic enzymes by angiotensin in cultured adrenal medullary cells. Molecu- lar mechanisms and nature of second messenger systems. J Eiol Chem. 1990a; 265: 4694-4702. Bird IM, Mason JI, Oka K, Rainey WE. Angiotensin II stimulates an increase in CAMP and expression of 17 alpha-hydroxylase cytochrome P450 in fetal bovine adrenocortical cells. Endocrino- Iogv 1993: 132: 932-934. Low BC. Ross IK, Grigor MR. Angiotensin II stimulates glucose transport activity in cultured vascular smooth muscle cells. J Biol Chem. 1992; 267: 20740-20745. Wolf G, Haberstroh LJ, Neilson EG. Angiotensin II stimulates the proliferation and biosynthesis of type I collagen in cultured murine mesangial cells. Am J Puthol. 1992; 140: 95- 107. Kato H. Suzuki H, Tajima S, Ogata Y, Tominaga T, Sato A, Saruta T. Angiotensin II stimulates collagen synthesis in cultured vascular smooth muscle cells. J Hypertens. 1991; 9: 17 -22. Scott-Burden T, Resink TJ, Hahn AW. Buhler FR. Induction of thrombospondin expression in vascular smooth muscle cells by angiotensin II. J Curdiovusc Pharmacol. 1990: 16 (suppl. 7): Sl7 so. Bernstein KE. Alexander RW. Counterpoint: molecular analysis of the angiotensin II receptor. Endo Rw. 1992; 13: 381-386. C’att K. Abbott A. Molecular cloning of angiotensin II receptors may presage further receptor subtypes. Trends Pharmacol Sri. 1991; 12: 279-281. lnagami T, Iwai N, Sasaki K, Guo D-F, Furuta H, Yamano Y, Badhan S, Chaki S, Makito N. Badr K. Angiotensin II receptors: cloning and regulation. Drug Res. 1993; 43: 226-228. Zhou J. Ernsberger, Douglas JG. A novel angiotensin receptor subtype in rat mesangium. coupling to adenylate cyclase. Hvpertension 1993; 21: 1035-1038. Gunther S. Characterization of angiotensin II receptor subtypes in rat liver. J Biol Chem. 1982: 259: 7622-7629. Chang RSL, Lotti VJ. Two distinct angiotensin II receptor binding sites in rat adrenal revealed by new selective nonpeptide ligands. Mol Phnrmarol. 1990; 29: 347-35 1. Chiu AT. Herblin WF, McCall DE, Ardecky RJ, Carini DJ, Duncia JV, Pease LJ, Wong PC, Wexler RR, Johnson AL. Timmermans PBMWM. Identification of angiotensin II receptor subtypes, Biochcm Bioph.vs RES Commun. 1989; 165: 196203. Hodges JC. Hamby JM. Blankley CJ. Angiotensin II receptor binding inhibitors. Drugs Future 1992; 17: 575-593. Whitebread S, Mele M, Kamber B, de Gasparo M. Preliminary biochemical characterization of two angiotensin II receptor subtypes. Biochem Biophys Res Commun. 1989; 163: 284291. Viswanathan M. Tsutsumi K, Correa FM, Saavedra JM. Changes in expression of angiotensin receptor subtypes in the rat aorta during development. Biochem Biophys Res Commun. 199 I: 179: 1361 -1367. Cook VI, Grove KL, McMenamin KM, Carter MR. Harding JW, Speth RC. The AT2 angiotensin receptor subtype predominates in the 18 day gestation fetal rat brain. Bruin Res. 1991; 560: 334 336. Grady EF. Sechi LA. Griffin CA, Schambelan M, Kalinyak JE. Expression of AT2 receptors in the developing rat fetus. J Clin Invesr. 1991: 88: 921-933. Millan MA. Jacobowitz DM, Aguilera G, Catt KJ. Differential distribution of ATI and AT2 angiotensin II receptor subtypes in the rat brain during development. Proc Nurl AcadSci USA. 1991; 88. 1144&-11444. Dudley DT. Hubbell SE. Summerfelt RM. Characterization of angiotensin II (AT2) binding sites in RiT3 cells. Mol Pharmacol. 1991; 40: 360-367. Leung KH, Roscoe WA, Smith RD, Timmermans PB. Chiu AT. Characterization of biochemical


responses of angiotensin II (AT2) binding sites in the rat pheochromocytoma PC12W cells. Eur J Pharmacol. 1992; 227: 63310.

152. Puce11 AG, Hodges JC, Sen I, Bumpus FM, Husain A. Biochemical properties of the ovarian granulosa cell type 2-angiotensin II receptor. Endocrinology 1991; 128: 1947-1959.

153. Webb ML, Lui EC, Cohen RB, Hedberg A, Bogosian EA, Monshizadegan H, Molloy C, Serafino R, Moreland S, Murphy TJ, et al. Molecular characterization of angiotensin II type II receptors in rat pheochromocytoma cells. Peptides 1992; 13: 4999508.

154. Buisson B, Bottari SP. de Gasparo M, Gallo-Payet N, Payet MD. The angiotensin AT2 receptor modulates T-type calcium current in non-differentiated NC10815 cells. FEBS Letf. 1992; 309: 161- 164.

155. Gyurko R, Kimura B, Kurian P, Crews FT, Phillips MI. Angiotensin II receptor subtypes play opposite roles in regulating phosphatidylinositol hydrolysis in rat skin slices. Biochem Bioph.vs Res Commun. 1992; 186: 2855292.

156. Bottari SP, King IN, Reichlin S, Dahlstroem I, Lydon N, de GM. The angiotensin AT2 receptor stimulates protein tyrosine phosphatase activity and mediates inhibition of particulate guanylate cyclase. Biochem Biophys Res Commun. 1992; 183: 206211.

157. Keiser JA, Major TC, Lu GH, Davis, LS, Panek RL. Is there a functional cardiovascular role for AT2 receptors? Drug Dev. Res. 1993; 29: 94-99.

158. Scheuer DA, Perrone MH. Angtiotensin type 2 receptors mediate depressor phase of biphasic pressure response to angiotensin. Am J Physiol. 1993; 264: R917-R923.

159. Jaiswal N, Tallant EA, Jaiswal RK, Diz DI, Ferrario CM. Differential regulation of prostaglandin synthesis by angiotensin peptides in porcine aortic smooth muscle cells: subtypes of angiotensin receptors involved. J Pharmacol Exp Ther. 1993; 265: 664673.

160. Janiak P, Pillon A, Prost JF, Vilaine JP. Role of angiotensin subtype 2 receptor in neointima formation after vascular injury. Hyperfension 1992; 20: 737-745.

161. Pratt RE, Wang D, Hein L, Dzau VJ. The AT2 isoform of the angiotensin receptor mediates myointimal hyperplasia following vascular injury. Hyperfension 1992; 20: 432.

162. Reagan LP, Theveniau M, Yang X-D, Siemans IR, Yee DK. Reisine T, Fluharty SJ. Development of polyclonal antibodies against angiotensin type 2 receptors. Proc Nat1 Acad Sci USA. 1993; 90: 79567960.

162a. Mukoyama M, Nakajima M, Horiuchi M, Sasamura H, Pratt RE, Dzau VJ. Expression cloning of type 2 angiotensin II receptor reveals a unique class of seven-transmembrane receptors. J Biol Chem. 1993;268:24539-24542.

162b. Kambayashi Y, Rardhan S, Takahashi K, Tcuzuki S, Inui H, Hamakubo T, Inagami T. Molecular

163.

164.

165.

166.

167.

168.

169.

170.

171.

cloning of a novel angiotensin II receptor isoform involved in phosphotyrosine phosphatase inhibition. J Biol Chem. 1993; 268: 24543-24546. Jackson TR, Blair LA, Marshall J, Goedert M. Hanley MR. The mas oncogene encodes an angiotensin receptor. Nature 1988; 335: 437440. Jackson TR, Hanley MR. Tumor promoter 12-0-tetradecanoylphorbol 13-acetate inhibits mas/ angiotensin receptor-stimulated inositol phosphate production and intracellular Ca2’ elevation in the 4OlL-C3 cell line. FEBS Lett. 1989; 251: 27-30. Andrawis NS. Dzau VJ, Pratt RE. Autocrine stimulation of mas oncogene leads to altered growth control. Cell Biol Int Rep. 1992; 16: 547-556. Bunnemann B, Fuxe K, Metzger R, Mullins J, Jackson TR, Hanley MR. Ganten D. Autoradio- graphic localization of mas proto-oncogene mRNA in adult rat brain using in situ hybridization. Neurosci Letr. 1990; 114: 147-153. Hanley MR. Molecular and cell biology of angiotensin receptors. J Cardiovasc Pharmacol. 1991; 18 (Suppl. 2): s7-s13. Teutsch B, Bihoreau C, Monnot C, Bernstein KE, Murphy TJ, Alexander RW, Corvol P, Clauser E. A recombinant rat vascular AT1 receptor confers growth properties to angiotensin II in Chinese hamster ovary cells. Biochem Biophys Res Commun. 1992; 187: 1381-1388. Bobik A, Campbell JH. Vascular derived growth factors: cell biology, pathophysiology. and pharmacology. Pharmacol Rev. 1993; 45: l-42. Charnley CJ, Campbell GR, Ross R. Phenotype-dependent response of cultured aortic smooth muscle to serum mitogens. J Cell Biol. 1981; 89: 379-383. Jackson CL, Schwartz SM. Pharmacology of smooth muscle replication. Hypertension 1992; 20: 713-736.

Control of Growth by Angiotensin II I Y3

172.

173.

174.

175.

176.

177.

178.

179.

180.

181.

182.

183.

184. 185.

186.

187.

188.

189.

190.

191.

192.

193.

194.

195.

196.

Dickson RB, Aitken S. Lippman ME. Assay of mitogen-induced effects on cellular incorporation ot precursors for scavenger, de nova, and net DNA synthesis. Methods Enzymol. 1987; 146: 329-340. Dubey RK. Roy A, Overbeck HW. Culture of renal arteriolar smooth muscle cells. Mitogenic responses to angiotensin II. Circ Res. 1991; 71: 1143-l 152. Wolthuis A, Boes A, Rodemann HP, Grond J. Vasoactive agents affect growth and protein synthesis of cultured rat mesangial cells. Kidnqv Inr. 1992; 41: 124-l 3 1. Ray PE, Aguilera G, Kopp JB, Horikoshi S, Klotman PE. Angiotensin II receptor-mediated proliferation of cultured human fetal mesangial cells. Kidney Inr. 1991; 40: 764771. Griffin SA, Brown WC, MacPherson F, McGrath JC, Wilson VG, Korsgaard N, Mulvany MJ. Lever AF. Angiotensin II causes vascular hypertrophy in part by a non-pressor mechanism. Hypertension 1991; 17: 626635. Schwartz SM, Heimark RL, Majesky MW. Developmental mechanisms underlying pathology ol arteries. Physiol Rev. 1990; 70: 921-961. Geisterfer AA, Peach MJ, Owens GK. Angiotensin II induces hypertrophy. not hyperplasia. of cultured rat aortic smooth muscle cells. Circ Res. 1988; 62: 749-756. Berk BC, Vekshtein V, Gordon HM, Tsuda T. Angiotensin II-stimulated protein synthesis in cultured vascular smooth muscle cells. Hypertension 1989; 13: 305-314. Bunkenburg B, van Amelsvoort T, Rogg H, Wood JM. Receptor-mediated effects of angiotensin II on growth of vascular smooth muscle cells from spontaneously hypertensive rats. Hypertension 1992; 20: 746754. Paquet JL. Baudouin LM, Brunelle G. Meyer P. Angiotensin II-induced proliferation of aortic myocytes in spontaneously hypertensive rats. J Hypertens. 1990; 8: 565-572. Scott-Burden T, Hahn AW, Resink TJ, Buhler FR. Modulation of extracellular matrix by angiotensin II: stimulated glycoconjugate synthesis and growth in vascular smooth muscle cells. J Cardiovasc Pharmacol. 1990a; 16 (Suppl. 4): S36S41. Lyall F. Morton JJ, Lever AF, Cragoe EJ. Angiotensin II activates Na+-Hi exchange and stimulates growth in cultured vascular smooth muscle cells. J Hypertens Suppl. 1988; 6: S438S44I. Massague J, Weinberg RA. Negative regulators of growth. Curr Opin Gene/ Dev. 1992; 2: 28832. Battegay EJ, Raines EW, Seifert RA, Bowen-Pope DF, Ross R. TGF-beta induces bimodal proliferation of connective tissue cells via complex control of an autocrine PDGF loop. Cell 1990; 63: 515 -524. Majack RA. Beta-type transforming growth factor specifies organizational behaviour in vascular smooth muscle cell cultures. J Cell Eiol. 1987; 105: 465471. Owens GK. Geisterfer AA, Yang YW, Komoriya A. Transforming growth factor-beta-induced inhibition and cellular hypertrophy in cultured vascular smooth muscle cells. J Cell Biol. 1988: 107: 771-780. Gibbons GH, Pratt RE, Dzau VJ. Vascular smooth muscle cell hypertrophy vs. hyperplasia. Autocrine transforming growth factor-beta 1 expression determines growth response to angiotensin II J C/in Invest. 1992; 90: 456461. Koibuchi Y, Lee WS, Gibbons GH, Pratt RE. Role of transforming growth factor-beta I in the cellular growth response to angiotensin II. Hypertension 1993; 21: 1046-1050. Miyazono K. Ichijo H, Heldin CH. Transforming growth factor-beta: latent forms, binding proteins and receptors. Growfh Factors 1993; 8: 1 I-22. Stouffer GA, Owens GK. Angiotensin II-induced mitogenesis of spontaneously hypertensive rat- derived cultured smooth muscle cells is dependent on autocrine production of transforming growth factor-/?. Circ Res. 1992; 70: 82&828. Stouffer GA, LaMarre J, Gonias SL, Owens GK. Activated cx2-macroglobulin and transforming growth factor-/31 induce a synergistic smooth muscle cell proliferative response. J Biol Chem. 1993: 268: 1834&18344. Chen R-W. Ebner R, Derynck R. Inactivation of the type II receptor reveals two receptor pathways for the diverse TGF-8 activities. Science 1993; 260: 1335-1338. Koff A, Ohtsuki M. Polyak K, Roberts JM, Massague J. Negative regulation of Cl in mammalian cells: inhibition of cyclin E-dependent kinase by TGF-beta. Science 1993; 260: 536539. Fagin JA. Forrester JS. Growth factors, cytokines, and vascular injury. Trend.y Cardiovasc Med. 1992; 2: 9&94. Daemen MJ, Lombardi DM. Bosman FT. Schwartz SM. Angiotensin II induces smooth muscle cell proliferation in the normal and injured rat arterial wall. Circ Res. 1991; 68: 45-56.

194

197. Viswanathan M, Stromberg C. Seltzer A, Saavedra JM. Balloon angioplasty enhances the expression of angiotensin II ATI receptors in neointima of rat aorta. J Clin Invesr. 1992; 90: 1707- 1712.

198.

199.

200.

201.

Rakugi H, Jacob HJ, Krieger JE, Ingelfinger JR, Pratt RE. Vascular injury induces angiotensinogen gene expression in the media and neointima. Circulation 1993; 87: 283-290. Shiota N, Okunishi H, Fukamizu A, Sakonjo H, Kikumori M, Nishimura T. Nakagawa T, Murakami K, Miyazaki M. Activation of two angiotensin-generating systems in the balloon-injured artery. FEBS Let/. 1993; 323: 239-242. Majesky MW, Lindner V, Twardzik DR, Schwartz SM. Reidy MA. Production of transforming growth factor beta1 during repair of arterial injury. J Ctin invest. 1991; 88: 904910. Capron L, Heudes D, Chajara A, Bruneval P. Effect of ramipril, an inhibitor of angiotensin converting enzyme. on the response of rat thoracic aorta to injury with a balloon catheter. J Cardiavnsc Pharmacol. 199 1; 18: 207-2 11.

202. Clowes AW, Clowes MM, Verge1 SC, Muller RK, Powell JS, Hefti F, Baumgartner HR. Heparin and cilazapril together inhibit injury-induced intimal hyperplasia. Hypertension 1991; 18 (Suppl. 4): 1165-1169.

203. Powell JS, Clozel JP, Muller RK, Kuhn H, Hefti F. Hosang M, Baumgartner HR. Inhibitors of angiotensin-converting enzyme prevent myointimal proliferation after vascular injury. Science 1989; 245: 186188.

204.

205.

206.

207.

208.

209.

Prescott MF, Webb RL, Reidy MA. Angiotensin-converting enzyme inhibitor versus angiotensin II. AT1 receptor antagonist. Effects on smooth muscle cell migration and proliferation after balloon catheter injury. Am J Puthol. 1991; 139: 1291-1296. Huber KC, Schwartz RS, Edwards WD, Camrud AR, Bailey KR, Jorgenson MA, Holmes DJ. Effects of angiotensin-converting enzyme inhibition on neointimal proliferation in a porcine coronary injury model. Am Heart J. 1993; 125: 695-701. Lam JY, Lacoste L, Bourassa MG. Cilazapril and early atherosclerotic changes after balloon injury of porcine carotid arteries [see comments]. Circulation 1992; 85: 1542-1547. Hanson SR, Powell JS, Dodson T, Lumsden A, Kelly AB, Anderson JS, Clowes AW, Harker LA. Effects of angiotensin-converting enzyme inhibition with cilazapril onintimal hyperplasia in injured arteries and vascular grafts in the baboon. Hypertension 1991; 18 (Suppl. 4): 1170-1176. Herrman J-PR, Hermans WRM. Vos J, Serruys PW. Pharmacological approaches to the prevention of restenosis following angioplasty, the search for the holy grail? Drugs 1993; 46:18-52. Okunishi H, Oka Y, Shiota N, Kawamoto T, Song K, Miyazaki M. Marked species-difference in the vascular angiotensin II-forming pathways: humans versus rodents. Jpn J Pharmacol. 1993; 62: 207- 210.

210.

211.

212.

Urata H, Boehm KD, Philip A, Kinoshita A, Gabrovsek .I, Bumpus FM, Husain A. Cellular localization and regional distribution of an angiotensin II-forming chymase in the heart. J Chin Invesl. 1993; 91: 1269-1281. Azuma H, Niimi Y, Hamasaki H. Prevention of intimal thickening after endothelial removal by a nonpeptide angiotensin II receptor antagonist, losartan. Br J Pharmacol. 1992; 106: 665-671. Kauffman RF, Bean JS. Zimmerman KM, Brown RF, Steinberg MI. Losartan, a nonpeptide angiotensin II (AngII) receptor antagonist, inhibits neointima formation following balloon injury to rat carotid arteries. Life Sci. 1991; 49: PL223-PL228. Laporte S, Escher E. Neointima formation after vascular injury is angiotensin II mediated. Biochem Biophys Res Commun. 1992; 187: 151&1516. Pan XM, Nelken N, Colyvas N, Rapp JH. Inhibition of injury induced intimal hyperplasia by saralasin in rats. J Vast Surg. 1992; 15: 693-698. Norbury C, Nurse P. Animal cell cycles and their control. Annu Rev Biochem. 1992; 61: 441470.

213.

214.

215. 216. Sherr, CJ. Mammalian Gl cyclins. Cell 1993: 73: 1059-1065.

W. R. Huckle and H. S. Earp

regulation of cell proliferation and growth by angiotensin ii

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