DDAH2 alleviates myocardial fibrosis in diabetic cardiomyopathy through activation of the DDAH/ADMA/NOS/NO pathway in rats

Zhu,Zhen‑Dong; Ye,Ji‑Ming; Fu,Xue‑Mei; Wang,Xue‑Chang; Ye,Ji‑Yun; Wu,Xin‑Ran; Hua,Peng; Liao,Yu‑Qiong; Xuan,Wei; Duan,Jin‑Lan; Li,Wei‑Yuan; Fu,Hui; Xia,Zhong‑Hua; Zhang,Xuan

doi:10.3892/ijmm.2018.4034

DDAH2 alleviates myocardial fibrosis in diabetic cardiomyopathy through activation of the DDAH/ADMA/NOS/NO pathway in rats

Authors:
- Zhen‑Dong Zhu
- Ji‑Ming Ye
- Xue‑Mei Fu
- Xue‑Chang Wang
- Ji‑Yun Ye
- Xin‑Ran Wu
- Peng Hua
- Yu‑Qiong Liao
- Wei Xuan
- Jin‑Lan Duan
- Wei‑Yuan Li
- Hui Fu
- Zhong‑Hua Xia
- Xuan Zhang
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Affiliations: Yunnan Research Center for Geriatric Diseases, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming Science and Technology University, Kunming, Yunnan 650032, P.R. China, Department of Pharmacy, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming Science and Technology University, Kunming, Yunnan 650032, P.R. China, Department of Geriatrics, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming Science and Technology University, Kunming, Yunnan 650032, P.R. China, Department of Pharmacy, the Third People's Hospital of Yunnan Province, The Second Affiliated Hospital of Dali University, Kunming, Yunnan 650011, P.R. China, Pathogenic Organisms Department of Experimental Center, School of Basic Medical Sciences, Kunming Medical University, Kunming, Yunnan 650500, P.R. China, Center Laboratory, The Third People's Hospital of Yunnan Province, The Second Affiliated Hospital of Dali University, Kunming, Yunnan 650011, P.R. China, Clinic Laboratory, The First People's Hospital of Yunnan Province, Affiliated Hospital of Kunming Science and Technology University, Kunming, Yunnan 650032, P.R. China, Clinical Medical College of Dali University, Dali, Yunnan 671003, P.R. China, School of Pharmaceutical Science and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan 650500, P.R. China
Published online on: December 18, 2018 https://doi.org/10.3892/ijmm.2018.4034
Pages: 749-760
Copyright: © Zhu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Diabetic cardiomyopathy (DCM) is a form of idiopathic heart disease, with signs including hypertrophy of myocardial cells, hypertension‑independent fibrosis and coronary artery disease. Considering the involvement of dimethylarginine dimethylaminohydrolase 2 (DDAH2) in diabetes, it was hypothesized that DDAH2 may be beneficial to cardiac function and myocardial fibrosis during the progression of DCM with involvement of the DDAH/asymmetric NG, NGdimethyl‑L‑arginine (ADMA)/nitric oxide synthase (NOS)/nitric oxide (NO) signaling pathway. Following establishment of diabetic rat models, diabetes‑related blood biochemical indices and cardiac function were measured in diabetic rats treated with lentivirus expressing DDAH2, short hairpin RNA against DDAH2, or L‑NNA (inhibitor of NOS) to identify the roles of DDAH2 in DCM. The functional roles of DDAH2 in DCM were further determined through detection of the levels of collagen I, matrix metalloproteinase 2 (MMP2) and tissue inhibitor of metalloproteinase 2 (TIMP2). The H9C2 myocardial cell line was selected for in vitro experiments. The effects of DDAH2 on the migration of myocardial cells under high glucose conditions were also examined. To further investigate the underlying regulatory mechanism of DDAH2 in DCM, the contents of ADMA and NO, and the activities of DDAH and NOS were observed. The DCM model rats treated with DDAH2 exhibited reduced left ventricular end‑diastolic pressure, and decreased blood glucose, total cholesterol, triglyceride, fasting blood glucose, and fasting insulin levels, but exhibited increased left ventricular systolic pressure and maximum rate of left ventricular pressure rise/fall levels in myocardial tissues. Myocardial cells under high glucose conditions treated with DDAH2 showed reductions in collagen I, MMP2 and TIMP2, indicating that DDAH2 reduced cell migration. Decreased levels of ADMA and NO but increased levels of DDAH and NOS were observed following treatment with DDAH2, indicating that the DDAH/ADMA/NOS/NO pathway was activated. These results reveal that the overexpression of DDAH2 attenuates myocardial fibrosis and protects against DCM through activation of the DDAH/ADMA/NOS/NO pathway in DCM rats. These results indicate that DDAH2 is a potential therapeutic candidate for the treatment of DCM.

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