Department of Nephrology, Charité- Universitätsmedizin Berlin, Campus Charité Mitte, Berlin, Germany.
Eur J Clin Invest. 2010 Mar;40(3):203-10. doi: 10.1111/j.1365-2362.2009.02251.x. Epub 2010 Jan 19.
Transgenic overexpression of human endothelin-2 in rats was used to characterize the contribution of endothelin to diabetic cardiomyopathy.
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.
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.
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.
通过在大鼠中过表达人内皮素-2，研究了内皮素对糖尿病心肌病的作用。
链脲佐菌素诱导糖尿病模型，建立转内皮素-2 基因大鼠及其相应对照品系。同时设立正常对照组，进行 6 个月的高血糖实验。观察心脏形态学和分子生物学改变。
两组转基因大鼠的血浆内皮素浓度均显著高于野生型大鼠（非糖尿病：3.5 ± 0.4 对 2.1 ± 0.2，P < 0.05；糖尿病：4.5 ± 0.4 对 2.5 ± 0.4 fmol/ml，P < 0.01）。糖尿病导致野生型和转基因大鼠心肌肥大，其中糖尿病转基因大鼠心肌间质组织体积密度最大（1.5 ± 0.07%），显著高于非糖尿病转基因大鼠（1.1 ± 0.03%）、非糖尿病野生型大鼠（0.8 ± 0.01%）和糖尿病野生型大鼠（1.1 ± 0.03%；P < 0.01）。在转内皮素-2 基因、糖尿病大鼠中，大冠状动脉和心肌内小动脉的肥大也呈现出类似的变化模式，且最为严重。内皮素-1、内皮素受体 A 和 B 的心肌 mRNA 表达在一定程度上受糖尿病或内皮素-2 过表达的影响，但不是以一种统一的方式。四组大鼠的血压无显著差异。
在大鼠中过表达人内皮素-2 基因可加重糖尿病心肌病，表现为更为严重的冠状动脉和心肌内血管肥大以及心肌间质纤维化。该转基因干预进一步独立地支持了内皮素在糖尿病心脏病变中具有血压非依赖性的有害作用。
