Functional, structural and molecular aspects of diastolic heart failure in the diabetic (mRen-2)27 rat

• Published in: Cardiovascular research Vol. 76; no. 2; pp. 280 - 291
• Main Authors: CONNELLY, K. A, KELLY, D. J, KRUM, H, GILBERT, R. E, ZHANG, Y, PRIOR, D. L, MARTIN, J, COX, A. J, THAI, K, FENELEY, M. P, TSOPORIS, J, WHITE, K. E
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-11-2007
• Subjects: Animals; Animals, Genetically Modified; Apoptosis; Biological and medical sciences; Cardiology. Vascular system; Diabetes Mellitus, Experimental - complications; Diabetes. Impaired glucose tolerance; Diastole; Disease Models, Animal; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Heart; Heart Failure - genetics; Heart Failure - pathology; Heart Failure - physiopathology; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Male; Medical sciences; Myocardium - pathology; Rats; Rats, Sprague-Dawley; Renin - genetics; Sarcoplasmic Reticulum Calcium-Transporting ATPases - analysis; Streptozocin; Transforming Growth Factor beta - analysis; Endocrinopathy; Heart failure; Rat; Diabetes mellitus; Contractile function; Rodentia; Cardiovascular disease; Renin-angiotensin system; Phlebology; Vertebrata; Renin angiotensin system; Mammalia; Heart disease; Animal; Fibrosis; Circulatory system; Diabetes; Cardiology
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1016/j.cardiores.2007.06.022

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.
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.
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-beta (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.
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.