title: Effects of transgenic endothelin-2 overexpression on diabetic cardiomyopathy in rats.
abstract: BACKGROUND
  Transgenic overexpression of human endothelin-2 in rats was used to characterize the contribution of endothelin to diabetic cardiomyopathy.
  
  
  METHODS
  Diabetes mellitus was induced by streptozotocin in transgenic rats and transgene-negative controls. Nondiabetic animals were included as well to form a 4-group study design. Heart morphological and molecular alterations were analysed following 6 months of hyperglycaemia.
  
  
  RESULTS
  Plasma endothelin concentrations were significantly higher in both transgenic groups than in wild-type groups (nondiabetic: 3.5 +/- 0.4 vs. 2.1 +/- 0.2, P < 0.05; diabetic: 4.5 +/- 0.4 vs. 2.5 +/- 0.4 fmol mL(-1), P < 0.01). Diabetes induced cardiac hypertrophy in both wild-type and transgenic rats and showed the highest myocardial interstitial tissue volume density in diabetic transgenic rats (1.5 +/- 0.07%) as compared with nondiabetic transgenic (1.1 +/- 0.03%), nondiabetic wild-type (0.8 +/- 0.01%) and diabetic wild-type rats (1.1 +/- 0.03%; P < 0.01 for all comparisons). A similar pattern with the most severe changes in the enothelin-2 transgenic, diabetic animals was observed for hypertrophy of the large coronary arteries and the small intramyocardial arterioles respectively. Cardiac mRNA expression of endothelin-1, endothelin receptors type A and B were altered in some degree by diabetes or transgenic overexpression of endothelin-2, but not in a uniform manner. Blood pressure did not differ between any of the four groups.
  
  
  CONCLUSIONS
  Overexpression of the human endothelin-2 gene in rats aggravates diabetic cardiomyopathy by more severe coronary and intramyocardial vessel hypertrophy and myocardial interstitial fibrosis. This transgenic intervention provides further and independent support for a detrimental, blood pressure-independent role of endothelins in diabetic cardiac changes.
authors.affiliation: Department of Nephrology, Charité- Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Liefeldt
authors.forename: B
authors.initials: B
authors.lastname: Rylski
authors.forename: F
authors.initials: F
authors.lastname: Walcher
authors.forename: J
authors.initials: J
authors.lastname: Manhart
authors.forename: S
authors.initials: S
authors.lastname: Kron
authors.forename: Y-W
authors.initials: YW
authors.lastname: Rosenke
authors.forename: M
authors.initials: M
authors.lastname: Paul
authors.forename: H-H
authors.initials: HH
authors.lastname: Neumayer
authors.forename: K
authors.initials: K
authors.lastname: Amann
authors.forename: H
authors.initials: H
authors.lastname: Peters
mesh_terms: D000818:Animals; D001160:Arterioles / Q000473:pathology; D001794:Blood Pressure; D009202:Cardiomyopathies / Q000209:etiology / Q000378:metabolism*; D003331:Coronary Vessels / Q000503:physiopathology; D048909:Diabetes Complications; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism; D019333:Endothelin-2 / Q000235:genetics / Q000378:metabolism*; D006984:Hypertrophy; D009206:Myocardium / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D055647:Rats, Transgenic / Q000378:metabolism; D017466:Receptors, Endothelin / Q000235:genetics / Q000378:metabolism; D013311:Streptozocin / Q000009:adverse effects
chemical_list: D019332:Endothelin-1; D019333:Endothelin-2; D012333:RNA, Messenger; D017466:Receptors, Endothelin; D013311:Streptozocin