Cardiomyocyte dimethylarginine dimethylaminohydrolase1 attenuates left-ventricular remodeling after acute myocardial infarction: involvement in oxidative stress and apoptosis.

Asymmetric dimethylarginine (ADMA) is a risk factor for heart diseases. Dimethylarginine dimethylaminohydrolase (DDAH) enzymes are key proteins for ADMA degradation. Endothelial DDAH1 is a vital regulator of angiogenesis. DDAH1 is also expressed in cardiomyocytes. However, the role of DDAH1 in cardiomyocytes needs further clarification. Herein, we used an inducible cardiac-specific DDAH1 knockdown mouse (cardiac DDAH1^-/-) to investigate the role of cardiomyocyte DDAH1 in left-ventricular (LV) remodeling after acute myocardial infarction (AMI). DDAH1flox/flox and α-MHC^MerCreMer mice were used to generate cardiac DDAH1^-/- mice. Deletion of DDAH1 in cardiomyocytes was confirmed by Western blotting. No significant differences were observed in plasma ADMA levels and LV function between cardiac DDAH1^-/- mice and control mice. Cardiac DDAH1^-/- mice showed aggravated LV remodeling 4 weeks after AMI, as demonstrated by a large infarct area and impaired LV function. The rate of cardiomyocyte apoptosis and level of oxidative stress were higher in the LV tissue of cardiac DDAH1^-/- mice than in that of control mice. However, treatment of cardiomyocytes with exogenous ADMA had no effect on reactive oxygen species levels or apoptosis sensitivity. Cardiac DDAH1^-/- LV tissue showed downregulated superoxide dismutase2 (SOD2) expression, and treatment of DDAH1^-/- cardiomyocytes with the SOD mimic tempol significantly attenuated apoptosis and levels under hypoxic conditions. Tempol administration also attenuated oxidative stress and apoptosis in cardiac DDAH1^-/- LV tissue and partially alleviated LV remodeling after AMI. DDAH1 in cardiomyocytes plays a vital role in attenuating LV remodeling after AMI by regulating intracellular duanyu1670 levels and apoptosis sensitivity via a SOD2-dependent pathway.

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