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Heart, Lung and Circulation Abstracts S2312008;17S:S219–S241

523Type 2 Diabetic Cardiomyopathy in db/db Mice is Asso-ciated with Progressive Cardiac Fibrosis, CardiomyocyteHypertrophy and Oxidative Stress

Rebecca Ritchie 1,∗, Tracey Julius 1, Keith Buxton 1, Qi Xu 1,Helen Kiriazis 1, Julie McMullen 1, Josephine Forbes 1,XiaoJun Du 1, David Kaye 1, Greg Tesch 2

1 Baker Heart Research Institute, Melbourne, Victoria, Aus-tralia; 2 Monash Medical Centre, Clayton, Victoria, Australia

Diabetic patients often develop a specific cardiomyopa-thy, characterized by structural remodelling and diastolicdysfunction. We sought to characterize the timeline ofdevelopment of cardiomyocyte hypertrophy and cardiacfibrosis in the db/db mouse model of type 2 diabetes(T2DM), and to determine the role of oxidative stressin this process. Progressive increases in cardiomyocytewidth (on H&E stained ventricular sections) and colla-gen deposition (on picrosirius red stained sections) wasevident in male and female db/db mice at 10, 14 and 18-weeks of age compared to their 18-wk nondiabetic db/+counterparts (n = 11 mice/age and gender group, exceptn = 7 female db/+). These changes mirrored the time-course of T2DM (hyperglycaemia, and elevation in HbA1cand bodyweight). Myocardial gene expression of both �-myosin heavy chain gene and pro-collagen III also tendedto increase in db/db mice with age. Preliminary resultsiw(flioVeMt(mpcptfc

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524Further Characterisation of Opioid-Mediated SustainedLigand Preconditioning

Jason Peart 1,∗, Garrett Gross 2, John Headrick 1

1 Griffith University, Southport, QLD, Australia; 2 MedicalCollege of Wisconsin, Milwaukee, WI, United States

We previously described a model whereby prolongedexposure to morphine (previously termed ‘chronicmorphine preconditioning’) results in a phenotype char-acterised by a lengthened window of protection, analternate signalling pathway to archetypal acute precondi-tioning, and protective efficacy in the aged heart. It is thisefficacy in the aged heart that presents ‘sustained ligand-activated preconditioning’ (SLP) as an attractive model forfurther detailed characterisation. To this end, we furtherexamined the opioid-induced SLP phenotype through aLangendorff-perfused mouse heart model subjected to25 min ischemia and 45 min reperfusion.From this characterisation, we report an apparent man-ifestation of the SLP phenotype as early as 24 h.Importantly, we observe that 7 days following cessationof morphine SLP induction, hearts recover to 65 ± 6% ofpre-ischemic baseline function, compared to 41 ± 1% and79 ± 5% for placebo and SLP (with no agonist withdrawal),respectively.Consecutive treatment with a selective delta-, but notkibftAaacfhFumpTa

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ndicated that these structural changes were associatedith changes in myocardial function: diastolic dysfunction

echocardiography-derived LV E/A and e/a on Dopplerow and tissue Doppler were 15 ± 3% and 36 ± 14% lower

n db/db, respectively). There was also some evidencef systolic dysfunction, with fractional shortening andcfc decreased by ∼25%. Myocardial superoxide gen-ration was also increased in db/db mice, 2.0 ± 0.8-fold.any of these changes were improved by administra-

ion of the potent endogenous antioxidant, coenzyme Q10CoQ, 10 mg/(kg day), oral gavage) for 10-week. CoQ treat-

ent was also associated with improved (cardioprotective)hosphoinositide 3-kinase PI3K�/Akt signalling. In con-lusion, the current study presents new insight into therogression of, contributing mechanisms to, and poten-

ial antioxidant interventions to limit, the structural andunctional abnormalities in the T2DM mouse heart, whichan be reversed by antioxidant intervention.

oi:10.1016/j.hlc.2008.05.577

appa-, opioid antagonist abolished the morphine-nduced SLP. Similarly, 5-day infusion of a selective delta-,ut not kappa-, opioid agonist mimicked SLP recovery

rom ischemia and reperfusion, demonstrating the impor-ance of the delta opioid receptor.dditionally, SLP has an additive effect with acutedenosine treatment, unrelated to adenosine metabolisms administration of the non-metabolised analogue, 2-hloroadenosine produced similar results. Moreover, SLPurther increased functional recovery in A1AR transgenicearts.inally, micro-array analysis reveals transcriptional reg-lation of inflammation, differentiation, angiogenesis,etabolic pathway, and cell survival genes within the SLP

henotype.hese data further demonstrate the novel nature of SLPnd its cardioprotective properties.

oi:10.1016/j.hlc.2008.05.578