Eur J Clin Invest 2010; 40 (3): 203–210
Background Transgenic overexpression of human endothelin-2 in rats was used to characterize the contribution of endothelin to diabetic cardiomyopathy.
Materials and 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.