Angiotensin-(1-7) treatment mitigates right ventricular fibrosis as a distinctive feature of diabetic cardiomyopathy.
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 Ca(2+)-ATPase. Thus RV fibrosis and dysfunction plays a central role in DCM, and ANG-(1-7) mitigates diabetes-induced RV alterations.
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China.
Pan-Pan
PP
Hao
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China.
Jian-Min
JM
Yang
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China.
Ming-Xiang
MX
Zhang
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China.
Kai
K
Zhang
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China.
Yu-Guo
YG
Chen
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China.
Cheng
C
Zhang
The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Qilu Hospital, Shandong University, Jinan, Shandong, People's Republic of China zhangyun@sdu.edu.cn.
Yun
Y
Zhang
D000803:Angiotensin I / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D018920:Coculture Techniques; D003094:Collagen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications; D003922:Diabetes Mellitus, Type 1 / Q000150:complications; D058065:Diabetic Cardiomyopathies / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D005355:Fibrosis; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008055:Lipids / Q000097:blood; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D017208:Rats, Wistar; D044139:Receptor, Angiotensin, Type 2 / Q000187:drug effects / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D018497:Ventricular Dysfunction, Right / Q000097:blood / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D016278:Ventricular Function, Right / Q000187:drug effects*; D020257:Ventricular Remodeling / Q000187:drug effects*
D001786:Blood Glucose; D008055:Lipids; D010446:Peptide Fragments; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D044139:Receptor, Angiotensin, Type 2; D043562:Receptors, G-Protein-Coupled; C508962:Tgfb1 protein, rat; D053773:Transforming Growth Factor beta1; D003094:Collagen; D000803:Angiotensin I; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C118790:angiotensin I (1-7)
angiotensin-(1–7); diabetic cardiomyopathy; heart failure; right ventriclular fibrosis