title: Functional, structural and molecular aspects of diastolic heart failure in the diabetic (mRen-2)27 rat.
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-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.
authors: University of Melbourne Department of Medicine, St. Vincent's Hospital, Victoria, Australia.
authors: K A
authors: KA
authors: Connelly
authors: D J
authors: DJ
authors: Kelly
authors: Y
authors: Y
authors: Zhang
authors: D L
authors: DL
authors: Prior
authors: J
authors: J
authors: Martin
authors: A J
authors: AJ
authors: Cox
authors: K
authors: K
authors: Thai
authors: M P
authors: MP
authors: Feneley
authors: J
authors: J
authors: Tsoporis
authors: K E
authors: KE
authors: White
authors: H
authors: H
authors: Krum
authors: R E
authors: RE
authors: Gilbert
mesh_terms: 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
chemical_list: D016212:Transforming Growth Factor beta; D013311:Streptozocin; D012083:Renin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases