Abstract
Pathological remodeling is the main detrimental complication after myocardial infarction (MI). Overproduction of reactive oxygen species (ROS) in infarcted myocardium may contribute to this process. Adequate exercise training after MI may reduce oxidative stress-induced cardiac tissue damage and remodeling. SET and MYND domain containing 1 (Smyd1) is a muscle-specific histone methyltransferase which is upregulated by resistance training, may strengthen sarcomere assembly and myofiber folding, and may promote skeletal muscles growth and hypertrophy. However, it remains elusive if Smyd1 has similar functions in post-MI cardiac muscle and participates in exercise-induced cardioprotection. Accordingly, we investigated the effects of interval treadmill exercise on cardiac function, ROS generation, Smyd1 expression, and sarcomere assembly of F-actin in normal and infarcted hearts. Adult male rats were randomly divided into five groups (n = 10/group): control (C), exercise alone (EX), sham-operated (S), MI induced by permanent ligation of left anterior descending coronary artery (MI), and MI with interval exercise training (MI + EX). Exercise training significantly improved post-MI cardiac function and sarcomere assembly of F-actin. The cardioprotective effects were associated with increased Smyd1, Trx1, cTnI, and α-actinin expression as well as upregulated ratio of phosphorylated AMP-activated protein kinase (AMPK)/AMPK, whereas Hsp90, MuRF1, brain natriuretic peptide (BNP) expression, ROS generation, and myocardial fibrosis were attenuated. The improved post-MI cardiac function was associated with increased Smyd1 expression. In cultured H9C2 cardiomyoblasts, in vitro treatment with H2O2 (50 µmol/L) or AMP-activated protein kinase (AMPK) agonist (AICAR, 1 mmol/L) or their combination for 4 h simulated the effects of exercise on levels of ROS and Smyd1. In conclusion, we demonstrated a novel role of Smyd1 in association with post-MI exercise-induced cardioprotection. The moderate level of ROS-induced upregulation of Smyd1 may be an important target for modulating post-MI cardiac function and remodeling.
Highlights
Myocardial infarction (MI) is usually initiated by myocardial ischemia, which induces overproduction of reactive oxygen species (ROS) in the ischemic region and surrounding myocardium [1,2]
It was recently demonstrated that SET and MYND domain containing 1 (Smyd1) was significantly upregulated in a mouse model of pressure overload-induced heart failure (HF) and that cardiac-specific Smyd1 knockout mice developed cardiomyocyte hypertrophy that led to significant structural remodeling and severe HF [14]
The purpose of our present study is to investigate the potential role of Smyd1 in post-MI ventricular remodeling and dysfunction and the potential benefits of post-MI exercise training by means of our established in vivo rat model of MI
Summary
Myocardial infarction (MI) is usually initiated by myocardial ischemia, which induces overproduction of reactive oxygen species (ROS) in the ischemic region and surrounding myocardium [1,2]. Whether acute MI-induced oxidative stress significantly alters cardiac expression of Trx and Smyd, which in turn modulate cardiomyocyte compensatory hypertrophy and/or pathological remodeling, remains largely unknown. Despite various modalities and mechanisms of exercise training having been studied in injured hearts [23,24,25], whether Smyd plays a role in cardioprotective effects of post-MI exercise training on oxidative stress and myocardial hypertrophy/remodeling in infarcted hearts remains elusive. Under this context, the purpose of our present study is to investigate the potential role of Smyd in post-MI ventricular remodeling and dysfunction and the potential benefits of post-MI exercise training by means of our established in vivo rat model of MI. The use of AICAR is to simulate a common action of various types of physical exercise, i.e., AMPK activation [26]
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