Angiotensin-Converting Enzyme-2 Overexpression Improves Left Ventricular Remodeling and Function in a Rat Model of Diabetic Cardiomyopathy
Angiotensin-Converting Enzyme-2 Overexpression Improves Left Ventricular Remodeling and Function in a Rat Model of Diabetic Cardiomyopathy
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血管紧张素转换酶 2 过度表达可改善糖尿病心肌病大鼠模型的左心室重塑和功能
DOI：
10.1016/j.jacc.2011.09.071
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发表时间：
2012-02-21
影响因子：
24
通讯作者：
Zhang, Yun
中科院分区：
文献类型：
--
作者：
Dong, Bo;Yu, Qing Tao;Zhang, Yun
目的 本研究旨在验证血管紧张素转换酶2（ACE2）过表达可能抑制糖尿病心肌病心肌胶原积聚并改善左心室（LV）重构和功能这一假说。
背景 高血糖激活肾素 - 血管紧张素系统，促进细胞外基质积聚以及心脏重构和功能障碍的进展。
方法 90只雄性Wistar大鼠随机分为治疗组（n = 80）和对照组（n = 10）。治疗组通过单次腹腔注射链脲佐菌素诱导糖尿病。链脲佐菌素注射12周后，治疗组大鼠进一步分为腺病毒 - ACE2组、腺病毒 - 增强型绿色荧光蛋白组、氯沙坦组和模拟组（每组n = 20）。评估左心室容积、左心室收缩和舒张功能、心肌纤维化程度、ACE2、血管紧张素转换酶和血管紧张素 -（1 - 7）的蛋白表达水平以及基质金属蛋白酶 - 2活性。进行心肌细胞和成纤维细胞培养以评估ACE2基因转染前后血管紧张素II和胶原蛋白的表达。
结果 ACE2基因转移4周后，与腺病毒 - 增强型绿色荧光蛋白组和对照组相比，腺病毒 - ACE2组ACE2表达增加，基质金属蛋白酶 - 2活性增强，左心室射血分数提高，左心室容积减小，心肌纤维化减轻，ACE、血管紧张素II和胶原蛋白表达降低。在改善左心室重构和功能以及降低胶原蛋白表达方面，ACE2优于氯沙坦。其可能的机制包括平衡向抑制成纤维细胞 - 心肌细胞关于胶原蛋白和转化生长因子 -β产生的相互作用转变，以及基质金属蛋白酶 - 2增强胶原蛋白降解。
结论 ACE2在糖尿病心肌病大鼠模型中抑制心肌胶原积聚并改善左心室重构和功能。因此，ACE2为糖尿病心肌病患者的治疗提供了一种有前景的方法。（《美国心脏病学会杂志》2012年；59：739 - 747）（C）2012美国心脏病学会基金会
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. (J Am Coll Cardiol 2012;59:739-47) (C) 2012 by the American College of Cardiology Foundation