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

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.

Transcriptional and Metabolomic Analysis of L-Arginine/Nitric Oxide Pathway in Inflammatory Bowel Disease and Its Association with Local Inflammatory and Angiogenic Response: Preliminary Findings

“…Accordingly, the presence of EMT markers has been demonstrated in fibrotic areas of IBD patients (reviewed in [37]). Recently, PRMT5 has been implicated in EMT by activating the Wnt/β-catenin pathway and inducing cancer cell migration [38]. PRMT5 might also contribute to hypermethylation of EMT-associated genes, the phenomenon observed in inflamed colonic mucosa in UC and speculated to contribute to the progression from ulcerative lesions to cancer [37].…”

“…FGF2 is implicated in fibrosis, although both profibrotic [51] and antifibrotic [52] activity has been attributed to this growth factor. The DDAHs association with FGF2 warrants further investigation as well, as DDAH2 has recently been shown to alleviate fibrosis associated with diabetic cardiomyopathy [38] and DDAH1 to inhibit the Wnt/β-catenin pathway, EMT, and gastric cancer cell migration [53]. Clouding matters, DDAH1 has promoted the migration of prostate cancer cells [54].…”

Exercise as A Potential Therapeutic Target for Diabetic Cardiomyopathy: Insight into the Underlying Mechanisms

“…T2DM-induced accumulation of extracellular matrix (ECM) proteins in the heart, also known as myocardial fibrosis, is the most marked histopathological change associated with DCM [8,14,15,[80][81][82][83][84]. Myocardial fibrosis leads to structural and functional changes in the heart through collagen deposition, interstitial fibrosis, and perivascular fibrosis [14].…”

“…Exercise is also reported to reduce myocardial fibrosis by lowering blood pressure [11]. Moreover, exercise has been shown to increase matrix metalloproteinase-2 and collagen degradation, while inhibiting myocardial fibrosis in obese mice [80,85]. The interaction between collagen and glucose leads to the formation of advanced glycation end products, which induce endothelial dysfunction and arterial and cardiac cirrhosis [15].…”

Exercise as A Potential Therapeutic Target for Diabetic Cardiomyopathy: Insight into the Underlying Mechanisms

“…T2DM-induced accumulation of extracellular matrix (ECM) proteins in the heart, also known as myocardial fibrosis, is the most marked histopathological change associated with DCM [8,14,15,[72][73][74][75][76]. Myocardial fibrosis leads to structural and functional changes in the heart through collagen deposition, interstitial fibrosis, and perivascular fibrosis [14].…”