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


CONCLUSIONS
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.
Connelly
K A
KA
University of Melbourne Department of Medicine, St. Vincent's Hospital, Victoria, Australia.
Kelly
D J
DJ
Zhang
Y
Y
Prior
D L
DL
Martin
J
J
Cox
A J
AJ
Thai
K
K
Feneley
M P
MP
Tsoporis
J
J
White
K E
KE
Krum
H
H
Gilbert
R E
RE
D000818:Animals; D030801:Animals, Genetically Modified; D017209:Apoptosis; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003971:Diastole; D004195:Disease Models, Animal; D006333:Heart Failure / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D009206:Myocardium / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000235:genetics*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000032:analysis; D013311:Streptozocin; D016212:Transforming Growth Factor beta / Q000032:analysis
D016212:Transforming Growth Factor beta; D013311:Streptozocin; D012083:Renin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases