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

Connelly, K. A., Kelly, D. J., Zhang, Y., Prior, D. L., Martin, J., Cox, A. J., Thai, K., Feneley, M. P., Tsoporis, J., White, K. E., Krum, H. and Gilbert, R. E. (2007) Functional, structural and molecular aspects of diastolic heart failure in the diabetic (mRen-2)27 rat. Cardiovascular Research, 76 2: 280-291. doi:10.1016/j.cardiores.2007.06.022


Author Connelly, K. A.
Kelly, D. J.
Zhang, Y.
Prior, D. L.
Martin, J.
Cox, A. J.
Thai, K.
Feneley, M. P.
Tsoporis, J.
White, K. E.
Krum, H.
Gilbert, R. E.
Title Functional, structural and molecular aspects of diastolic heart failure in the diabetic (mRen-2)27 rat
Journal name Cardiovascular Research   Check publisher's open access policy
ISSN 0008-6363
1755-3245
Publication date 2007-11-01
Sub-type Article (original research)
DOI 10.1016/j.cardiores.2007.06.022
Volume 76
Issue 2
Start page 280
End page 291
Total pages 12
Place of publication London, U.K.
Publisher Oxford University Press
Language eng
Subject 1102 Cardiovascular Medicine and Haematology
Formatted abstract
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.
© 2007 European Society of Cardiology. Published by Elsevier B.V.
Keyword Contractile function
Diabetes
Fibrosis
Heart failure
Renin-angiotensin system
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
School of Medicine Publications
 
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