期刊
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
卷 308, 期 9, 页码 H1007-H1019出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00563.2014
关键词
angiotensin-(1-7); diabetic cardiomyopathy; right ventriclular fibrosis; heart failure
资金
- National 973 Basic Research Program of China [2011CB503906, 2012CB518603]
- National High-tech Research and Development Program of China [2012AA02A510]
- Program of Introducing Talents of Discipline to Universities [B07035]
- State Program of National Natural Science Foundation of China for Innovative Research Group [81321061]
- State Key Program of National Natural Science of China [61331001]
- International Collaboration and Exchange Program of China [81320108004]
- National Natural Science Foundation of China [81400284, 81100207, 81173251, 81100102, 81270350, 81000126, 81000127]
- Natural Science Foundation of Shandong Province [ZR2014HM044, ZR2014HP045]
In diabetic patients, left ventricular (LV) remodeling is highly prevalent; however, little is known about the impact of diabetes on right ventricular (RV) structure and function. We recently found that overexpression of angiotensin (ANG)-converting enzyme 2 (ACE2), which metabolizes ANG-II to ANG-(1-7) and ANG-I to ANG-(1-9), may improve LV remodeling in diabetic cardiomyopathy (DCM). Here, we aimed to assess whether LV remodeling and dysfunction are paralleled by RV alterations and the effects of ANG-(1-7) on RV remodeling in DCM. After 12 wk of diabetes induced by a single intraperitoneal injection of streptozotocin, rats were treated with saline, ANG-(1-7), perindopril, ANG-(1-7) plus perindopril, ANG-(1-7) plus Mas receptor antagonist A779, or ANG-(1-7) plus ANG-II type 2 receptor antagonist PD123319 for 4 wk. RV remodeling in diabetic rats was indicated by fibrosis of the RV free wall in the absence of hypertrophy and apoptosis. Treatment with ANG-(1-7) prevented diabetes-induced RV fibrosis and dysfunction. ANG-(1-7) (800 ng.kg(-1).min(-1)) was superior to perindopril in improving RV fibrosis. The major mechanisms involved a complex interaction of ANG-II type 2 and Mas receptors for subsequent downregulation of ACE expression and activity and ANG-II type 1 receptor expression, as well as upregulation of ACE2 expression and activity and the expression of ANG-II type 2 receptor and sarco(endo) plasmic reticulum Ca2+-ATPase. Thus RV fibrosis and dysfunction plays a central role in DCM, and ANG-(1-7) mitigates diabetes-induced RV alterations.
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