CALL FOR PAPERS Cardiovascular Consequences of Obesity and Type 2 Diabetes Angiotensin-(1–7) treatment mitigates right ventricular fibrosis as a distinctive feature of diabetic cardiomyopathy

Hao PP, Yang JM, Zhang MX, Zhang K, Chen YG, Zhang C, Zhang Y. Angiotensin-(1–7) treatment mitigates right ventricular fibrosis as a distinctive feature of diabetic cardiomyopathy. Am J Physiol Heart Circ Physiol 308: H1007–H1019, 2015. First published February 27, 2015; doi:10.1152/ajpheart.00563.2014.—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 ·min ) 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 Ca -ATPase. Thus RV fibrosis and dysfunction plays a central role in DCM, and ANG-(1–7) mitigates diabetes-induced RV alterations.