Copyright © 2007, European Society of Cardiology
Functional, structural and molecular aspects of diastolic heart failure in the diabetic (mRen-2)27 rat
aUniversity of Melbourne Department of Medicine, St. Vincent's Hospital, Victoria, Australia
bSt. Michael's Hospital Toronto, Ontario, Canada
cCardiac Investigation Unit, St Vincent's Hospital Melbourne, Victoria Australia
dCardiac Mechanics Research Laboratory, St Vincent's Hospital and the Victor Chang Cardiac Research Institute, Victoria Street, Darlinghurst, Sydney, Australia
eEM Research Services, Newcastle University, Newcastle upon Tyne, UK
fNHMRC CCRE in Therapeutics, Department of Epidemiology and Preventive Medicine and Department of Medicine, Monash University, Faculty of Medicine, Nursing and Health Sciences, The Alfred, Victoria, Australia
*Corresponding author. St. Michael's Hospital, Room 6-138, 61 Queen St East, Toronto, Ontario, Canada, M5C 2T2. Tel.: +1 416 867 3747. richard.gilbert{at}utoronto.ca
Objective Diabetic cardiomyopathy is an increasingly recognized cause of cardiac failure despite preserved left ventricular systolic function. Given the over-expression of angiotensin II in human diabetic cardiomyopathy, we hypothesized that combining hyperglycaemia with an enhanced tissue renin-angiotensin system would lead to the development of diastolic dysfunction with adverse remodeling in a rodent model.
Methods Homozygous (mRen-2)27 rats and non-transgenic Sprague Dawley (SD) rats were randomized to receive streptozotocin (diabetic) or vehicle (non-diabetic) and followed for 6 weeks. Prior to tissue collection, animals underwent pressure–volume loop acquisition.
Results Diabetic Ren-2 rats developed impairment of both active and passive phases of diastole, accompanied by reductions in SERCA-2a ATPase and phospholamban along with activation of the fetal gene program. Structural features of diabetic cardiomyopathy in the Ren-2 rat included interstitial fibrosis, cardiac myocyte hypertrophy and apoptosis in conjunction with increased activity of transforming growth factor-β (p<0.01 compared with non-diabetic Ren-2 rats for all parameters). No significant functional or structural derangements were observed in non-transgenic, SD diabetic rats.
Conclusion These findings indicate that the combination of enhanced tissue renin-angiotensin system and hyperglycaemia lead to the development of diabetic cardiomyopathy. Fibrosis, and myocyte hypertrophy, a prominent feature of this model, may be a consequence of activation of the pro-sclerotic cytokine, transforming growth factor-beta, by the diabetic state.
KEYWORDS Heart failure; Renin-angiotensin system; Diabetes; Fibrosis; Contractile function
1 Both authors contributed equally in the preparation of this manuscript.
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