Effects of transgenic endothelin-2 overexpression on diabetic cardiomyopathy in rats.
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.
Liefeldt
L
L
Department of Nephrology, Charité- Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
Rylski
B
B
Walcher
F
F
Manhart
J
J
Kron
S
S
Rosenke
Y-W
YW
Paul
M
M
Neumayer
H-H
HH
Amann
K
K
Peters
H
H
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
D019332:Endothelin-1; D019333:Endothelin-2; D012333:RNA, Messenger; D017466:Receptors, Endothelin; D013311:Streptozocin