vascular biology of diabetes abdel moniem ibrahim ahmed, md professor of cardiovascular physiology...
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Vascular Biology Vascular Biology of Diabetesof Diabetes
Abdel Moniem Ibrahim Ahmed, MDAbdel Moniem Ibrahim Ahmed, MDProfessor of Cardiovascular Physiology
Cairo UniversityCairo University
Oct . 15 . 2003Oct . 15 . 2003
• Diabetes is a Cardiovascular disease.
• The concept of Endothelial Dysfunction (ED).
• Mechanisms of ED in diabetes:-
Initiation ( trigger ) phase of ED:
(Hyperglycemia - induced ED)
Transition from initiation to maintenance phase of ED:
(Formation of AGEs)
Maintenance phase of ED:
(Tightly linked to accumulation of AGEs)
• Hyperinsulinemia / insulin resistance and ED .
•Diabetes is a Cardiovascular disease.
• The concept of Endothelial Dysfunction.
• Mechanisms of ED in diabetes:-
Initiation ( trigger ) phase of ED:
(Hyperglycemia - induced ED)
Transition from initiation to maintenance phase of ED:
(Formation of AGEs)
Maintenance phase of ED:
(Tightly linked to accumulation of AGEs)
• Hyperinsulinemia / insulin resistance and ED .
Diabetes Mellitus
Independent major risk factor
Accelerated atherosclerosis
morbidity & mortality (80 %)
Cardiovascular Diseases
Acute Hyperglycemia
Normal Volunteers
Rapid BP elevation
Glucose levels trigger functional alterations in Glucose levels trigger functional alterations in vasomotor motions vasomotor motions
Marfella et al . Am J Physiol Endocrinol Metab . 1995 , 268 : E 1167 -
Diabetic Microangiopathy
At early stage
At later stages
Reversible changes :• Capillary press .• Blood flow . • EC permeability .
Irrevesible changes :• Thickening of the basement membrane • Extracellular accumulation of proteins
Arosio et al . Ann Ital Med Int . 1999 ; 14 (2) : 106-
• The onset of microvascular lesions in The onset of microvascular lesions in diabetes has been diabetes has been preceded bypreceded by endothelial dysfunction manifestations:endothelial dysfunction manifestations:
* ( ) in the vasodilatation response to vasoactive agents .
* Alterations in the antithrombotic properties.
Arosio et al . Ann Ital Med Int . 1999 ; 14 (2) : 106
In diabetic patients
ENDOTHELIUM
Pomilio et al . I pediatr Endocrinol Metab .2002 ; 15(4): 343-
The primary target of unbalanced glycemic control.
Involved in the pathogenesis of vascular complications.
Endothelial pathophysiologic balance
• Vasodilators– Nitric oxideNitric oxide– Prostacyclin– Endothelium derived
hyperpolarizing factor– C-natriuretic peptide
• Antithrombotic– Tissue type plasminogen activator– Prostacyclin– Nitric oxide
• Growth inhibitors– Nitric oxide– Prostacyclin– C-natriuretic peptide
• Inflammation inhibitors– Nitric oxide
• Vasoconstrictors– Endothelin-1– Angiotensin II– Endoperoxide (PGH2)– Thromboxane A2
• Prothrombotic– Plasminogen activator inhibitor-1– Thromboxane A2
• Growth promotors– Superoxide radicals– Endothelin– Angiotenisn II
• Inflammation promotors– Superoxide and other free radicals– Tumor necrosis factor-alpha
• Diabetes is a Cardiovascular disease.
•The concept of Endothelial Dysfunction.
• Mechanisms of ED in diabetes:-
Initiation ( trigger ) phase of ED:
(Hyperglycemia - induced ED)
Transition from initiation to maintenance phase of ED:
(Formation of AGEs)
Maintenance phase of ED:
(Tightly linked to accumulation of AGEs)
• Hyperinsulinemia / insulin resistance and ED .
HyperglycemiaAdvanced Glycosylation End
Products Oxidized Lipoproteins
Insulin Resistance
SMC MIGRATION,PROLIFERATION&
ECM PRODUCTION
Expression ofgrowth factors&
mitogens
EDRFPGI2
Leukocyteadhesion molecules& chemoattractantsAltered
junctions &transport
Cell surfaceprocoagulant
activity
INCREASEDPROTHROMBOTIC
ACTIVITY
IMPAIRED VASORELAXATION(VASOSPASM)
INCREASEDPERMEABILITY
& TRAPPING of LDL
INCREASEDLEUKOCYTE
RECRUITMENT
“ EC - dependent vasorelaxation
( flow - mediated dilatation )by using echo Doppler has remained
the gold standard in assessing endothelial function & dysfunction .”
“ EC - dependent vasorelaxation
( flow - mediated dilatation )by using echo Doppler has remained
the gold standard in assessing endothelial function & dysfunction .”
Goligorsky et al . Hypertension .2001, 37 [part2] : 744-748.
Endothelial Nitric Oxide Production
ecNOS
ACUTE CHRONIC
L-arg
L-arginine citrullineecNOS
[Ca+2, IP3]
Acetylcholine(other
mediators)
LSS[NO/EDRF]
TARGET CELLS(SMC, EC, PLATELETS)
LSSGrowth Factors
GTP VSMc c GMP SM relaxation
(+) Guanylyl cyclase
• Diabetes is a Cardiovascular disease.
• The concept of Endothelial Dysfunction.
•Mechanisms of ED in diabetes:- Initiation ( trigger ) phase of ED:
(Hyperglycemia - induced ED)
Transition from initiation to maintenance phase of ED:
(Formation of AGEs)
Maintenance phase of ED:
(Tightly linked to accumulation of AGEs)
• Hyperinsulinemia / insulin resistance and ED .
Proposal consequence Proposal consequence ( ( transient & cumulative) of hyperglycmic transient & cumulative) of hyperglycmic episodes on vascular wall . episodes on vascular wall .
Goligorsky et al . Hypertension .2001; 37 [part2] : 744
“ “ The ED initiation events is linked to scavenging The ED initiation events is linked to scavenging
of NO by glucose of NO by glucose ( NO bioavailability ) ( NO bioavailability ) during during
transient episodes of hyperglycemia ” transient episodes of hyperglycemia ”
Acute Hypertensive response
(-) Vasorelaxation 15 min. after hyperglycemia
NO Bioavailability
(+) Platelet reactions prothrmbotic activity(+) (MN) leukocyte chemotaxis & activation(+) Express . of leukocyte - CAMs (+) VSMC migration & proliferation
Acceleration of Atherosclerosis Acceleration of Atherosclerosis Brodsky et al . Am J Physiol Renal Physiol . 2001; 280: F 480-
NO scavenging)Chronic(
• Diabetes is a Cardiovascular disease.
• The concept of Endothelial Dysfunction.
•Mechanisms of ED in diabetes:- Initiation ( trigger ) phase of ED:
(Hyperglycemia - induced ED)
Transition from initiation to maintenance phase of ED:
(Formation of AGEs)
Maintenance phase of ED:
(Tightly linked to accumulation of AGEs)
• Hyperinsulinemia / insulin resistance and ED .
Acute Hyperglycemia
In healthy subjects
Mitochondrial superoxide (O2.-) production
ROS + NO
Peroxynitrites (ineffective)
Plasma nitrotyrosine (marker of oxid . Stress )
(+)
Marfella et al . JCI . 2001 , 108 (4) : 635
NO Bioavailability
Aging
Non-enzymatic reaction
Ambient glucose Primary amino acid groups on protein
Maillard reaction
Amadoric products
Dehydration
Fragmentation
AGEs in the Sub-EC Compartment
Friedman . Nephrol Dial Transport . 1999; 14 [Suppl 3] : 1-9
Tissue deposition
Hyperglycemia in Diabetes
Hyperglycemia in Diabetes
AGEs
Quench NO activityBind with their receptors RAGE
(EC, VSMC, Macrophages)
ROS NO Bioavailability
Tan et al . Diabetic Care . 2002; 25 (6): 1055
AGE - RAGE interaction is a
potential source for cell-
mediated oxidation & lipid
peroxidation
AGE - RAGE interaction is a
potential source for cell-
mediated oxidation & lipid
peroxidation
Diaz et al. NEJM. 1997,337)6( : 408
Oxidative-modification hypothesisOxidative-modification hypothesisOxidative-modification hypothesisOxidative-modification hypothesis
Hyperglycemia
Glucose – induced O2
.-Mitochondrial O2
.-over
Diacylglycerol (DAG)
Protein kinase C (PKC) activation
(-) PI3 kinase- mediated eNOS(+) (+) NAD(P) H oxidase
ROS
Beckman et al . Circ Res . 2002 ; 90 : 107-
NO Bioavailability
• Diabetes is a Cardiovascular disease.
• The concept of Endothelial Dysfunction.
•Mechanisms of ED in diabetes:- Initiation ( trigger ) phase of ED:
(Hyperglycemia - induced ED)
Transition from initiation to maintenance phase of ED:
(Formation of AGEs)
Maintenance phase of ED:
(Tightly linked to accumulation of AGEs)
• Hyperinsulinemia / insulin resistance and ED .
AGEs
Consume EC-derived NO Quench NO Activity
Extracellular matrix & physico-chemical changes
Goligorsky et al . Hypertension . 2001 ; 37 [part 2]
Functional NO deficiency
Deficiency of
Angiogenic response
(+) fibroblast proliferation
Collagen -to- collagen cross linking & tissue rigidity
Vascular Complications of Diabetes Vascular Complications of Diabetes
Proposed pathophysiological mechanisms acting during maintenance Proposed pathophysiological mechanisms acting during maintenance phase of ED . phase of ED .
Proposed pathophysiological mechanisms acting during maintenance Proposed pathophysiological mechanisms acting during maintenance phase of ED . phase of ED .
Induction of TGF - “chemotactic factor”
Hyperglycemia
VSMC migration
Atherosclerosis
Tan et al . Diabetic care . 2002 ; 25(6) : 1055
NF- B (+)
( ) ET-1 prod.
AGEs(+)
(+)
(+)
Clinical manifestations of diabetic nephropathy and potenial role of EDClinical manifestations of diabetic nephropathy and potenial role of EDClinical manifestations of diabetic nephropathy and potenial role of EDClinical manifestations of diabetic nephropathy and potenial role of ED
• Diabetes is a Cardiovascular disease.
• The concept of Endothelial Dysfunction.
• Mechanisms of ED in diabetes:-
Initiation ( trigger ) phase of ED:
(Hyperglycemia - induced ED)
Transition from initiation to maintenance phase of ED:
(Formation of AGEs)
Maintenance phase of ED:
(Tightly linked to accumulation of AGEs)
• Hyperinsulinemia/insulin resistance and ED .
Cluster of Metabolic & CV Abnormalities
Metabolic Syndrome
Insulin Resistance Endothelium
Common dominatorTarget of Insulin’s action on
vasomotility
Insulin
Protective effects Deleterious effects
• (+)VEGF .
• (+) ET-1 .
• Salt - sensitive HTN
* Vicent et al . TCI . 2003 , III (9) : 1373- * Ogihara et al . Diabetes . 2001 , 50 : 573-
• (-) apoptosis
• (+) NO prod.
Insulin Resistance
(+) PKC in vascular tissues
(-) PI-3 Kinase
(-) eNOS express.
Modulates vascular tone
Kuboki et al Circulation . 2000 ; 101 : 676 -
Hyperinsulinemia
Prolonged exposure
(-) EC- dependent VD
ED
O2.-
Vit. C
(Antioxidant)
(+) NAD(P) H oxidase express .
(+) E T-1
(+)
Arcaro et al . Circulation . 2002 ; 105 : 576
• Diabetes is a chronic vascular disease in which disordered glucose homeostasis triggers endothelial dysfunction of every organ, deriving, in part, from vascular disturbance.
• Diabetes is a chronic vascular disease in which disordered glucose homeostasis triggers endothelial dysfunction of every organ, deriving, in part, from vascular disturbance.
Conclusion
(+)(+) microvascular & macrovascular complications
Glycemic control
(-) (-) macrovascular & microvascular diseases
Gerich . Arch Intern Med . 2003 . 9 ; 16B (11) : 1306
Conclusion
• Understanding the mechanism(s) by which acute hyperglycemia induces ED in DM may lead to secondary preventive strategies to reduce CV morbidity and mortality in this highly prevalent disease .
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