- 作者：Bo Dong ; MD ; PhD?/sup> ; &dagger ; ; Qing Tao Yu ; MD?/sup> ; &Dagger ; ; Hong Yan Dai ; MD?/sup> ; Yan Yan Gao ; MD?/sup> ; Zhao Li Zhou ; MD?/sup> ; Lei Zhang ; MD ; PhD?/sup> ; Hong Jiang ; PhD?/sup> ; Fei Gao ; MD ; PhD?/sup> ; Shu Ying Li ; MD ; PhD?/sup> ; Yue Hui Zhang ; MD?/sup> ; Hong Jun Bian ; MD ; PhD?/sup> ; Chun Xi Liu ; MD?/sup> ; Nan Wang ; MD?/sup> ; Hui Xu ; MD?/sup> ; Chun Ming Pan ; MD§ ; ; Huai Dong Song ; MD ; PhD§ ; ; Cheng Zhang ; MD ; PhD?/sup> ; zhangcheng8003@yahoo.cn ; Yun Zhang ; MD ; PhD?/sup>
- 关键词：angiotensin-converting enzyme 2 ; angiotensin II ; diabetic cardiomyopathy ; gene therapy ; heart failure
- 刊名：Journal of the American College of Cardiology
- 出版年：2012
- 出版时间：21 February, 2012
- 年：2012
- 卷：59
- 期：8
- 页码：739-747
- 全文大小：2746 K
Objectives
The aim of this study was to test the hypothesis that angiotensin (Ang)-converting enzyme-2 (ACE2) overexpression may inhibit myocardial collagen accumulation and improve left ventricular (LV) remodeling and function in diabetic cardiomyopathy.Background
Hyperglycemia activates the renin-Ang system, which promotes the accumulation of extracellular matrix and progression of cardiac remodeling and dysfunction.
Methods
Ninety male Wistar rats were divided randomly into treatment (n = 80) and control (n = 10) groups. Diabetes was induced in the treatment group by a single intraperitoneal injection of streptozotocin. Twelve weeks after streptozotocin injection, rats in the treatment group were further divided into adenovirus-ACE2, adenovirus-enhanced green fluorescent protein, losartan, and mock groups (n = 20 each). LV volume; LV systolic and diastolic function; extent of myocardial fibrosis; protein expression levels of ACE2, Ang-converting enzyme, and Ang-(1-7); and matrix metalloproteinase-2 activity were evaluated. Cardiac myocyte and fibroblast culture was performed to assess Ang-II and collagen protein expression before and after ACE2 gene transfection.
Results
Four weeks after ACE2 gene transfer, the adenovirus-ACE2 group showed increased ACE2 expression, matrix metalloproteinase-2 activity, and LV ejection fractions and decreased LV volumes, myocardial fibrosis, and ACE, Ang-II, and collagen expression in comparison with the adenovirus-enhanced green fluorescent protein and control groups. ACE2 was superior to losartan in improving LV remodeling and function and reducing collagen expression. The putative mechanisms may involve a shift in balance toward an inhibited fibroblast-myocyte cross-talk for collagen and transforming growth factor-beta production and enhanced collagen degradation by matrix metalloproteinase-2.
Conclusions
ACE2 inhibits myocardial collagen accumulation and improves LV remodeling and function in a rat model of diabetic cardiomyopathy. Thus, ACE2 provides a promising approach to the treatment of patients with diabetic cardiomyopathy.