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

Basic Res Cardiol. 2018 Jun 11;113(4):28. doi: 10.1007/s00395-018-0685-y.

Abstract

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-MHCMerCreMer 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 (ROS) 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 ROS 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 ROS levels and apoptosis sensitivity via a SOD2-dependent pathway.

Keywords: Acute myocardial infarction; Apoptosis; Dimethylarginine dimethylaminohydrolase; Left-ventricular remodeling; Reactive oxygen species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / deficiency
  • Amidohydrolases / genetics
  • Amidohydrolases / metabolism*
  • Animals
  • Antioxidants / pharmacology
  • Apoptosis* / drug effects
  • Arginine / analogs & derivatives
  • Arginine / blood
  • Cells, Cultured
  • Cyclic N-Oxides / pharmacology
  • Disease Models, Animal
  • Mice, Knockout
  • Myocardial Infarction / drug therapy
  • Myocardial Infarction / enzymology*
  • Myocardial Infarction / pathology
  • Myocardial Infarction / physiopathology
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / enzymology*
  • Myocytes, Cardiac / pathology
  • Oxidative Stress* / drug effects
  • Reactive Oxygen Species / metabolism
  • Signal Transduction
  • Spin Labels
  • Superoxide Dismutase / metabolism
  • Ventricular Function, Left* / drug effects
  • Ventricular Remodeling* / drug effects

Substances

  • Antioxidants
  • Cyclic N-Oxides
  • Reactive Oxygen Species
  • Spin Labels
  • N,N-dimethylarginine
  • Arginine
  • Superoxide Dismutase
  • superoxide dismutase 2
  • Amidohydrolases
  • dimethylargininase
  • tempol