Abstract
BackgroundThymosin beta-4 (Tβ4) is a ubiquitous protein with many properties relating to cell proliferation and differentiation that promotes wound healing and modulates inflammatory mediators. The mechanism by which Tβ4 modulates cardiac protection under oxidative stress is not known. The purpose of this study is to dissect the cardioprotective mechanism of Tβ4 on H2O2 induced cardiac damage.MethodsRat neonatal cardiomyocytes with or without Tβ4 pretreatment were exposed to H2O2 and expression of antioxidant, apoptotic, and anti-inflammatory genes was evaluated by quantitative real-time PCR and western blotting. ROS levels were estimated by DCF-DA using fluorescent microscopy and fluorimetry. Selected antioxidant, anti-inflammatory and antiapoptotic genes were silenced by siRNA transfections in neonatal cardiomyocytes and effect of Tβ4 on H2O2-induced cardiac damage was evaluated.ResultsPre-treatment of Tβ4 resulted in reduction of the intracellular ROS levels induced by H2O2 in cardiomyocytes. Tβ4 pretreatment also resulted in an increase in the expression of antiapoptotic proteins and reduction of Bax/BCl2 ratio in the cardiomyocytes. Pretreatment with Tβ4 resulted in stimulating the expression of antioxidant enzymes copper/zinc SOD and catalase in cardiomyocytes at both transcription and translation levels. Tβ4 treatment resulted in the increased expression of anti-apoptotic and anti-inflammatory genes. Silencing of Cu/Zn SOD and catalase gene resulted in apoptotic cell death in the cardiomyocytes which was prevented by treatment with Tβ4.ConclusionThis is the first report that demonstrates the effect of Tβ4 on cardiomyocytes and its capability to selectively upregulate anti-oxidative enzymes, anti-inflammatory genes, and antiapoptotic enzymes in the neonatal cardiomyocytes thus preventing cell death thereby protecting the myocardium. Tβ4 treatment resulted in decreased oxidative stress and inflammation in the myocardium under oxidative stress.
Highlights
Adverse cardiac remodeling is a detrimental process accountable for the development of various cardiac diseases including myocardial infarction, cardiac hypertrophy and heart failure
Cardiomyocytes were treated with increasing doses of H2O2 and, cell viability was determined over a period of 24 hours
Pretreatment with Thymosin beta-4 (Tb4) (1 mg/mL) prevented the myocyte cell death by 23.4% (p,0.05), compared to the H2O2-treated group indicating a protective role of Tb4 in cardiomyocytes
Summary
Adverse cardiac remodeling is a detrimental process accountable for the development of various cardiac diseases including myocardial infarction, cardiac hypertrophy and heart failure. The mechanisms underlying the cardiac remodeling are multi-factorial, current evidences suggest that oxidative stress plays a critical role in the process. Oxidative stress is defined as an imbalance in antioxidant defense mechanism that elicits the production of reactive oxygen species (ROS) [1,2,3,4]. ROS are primarily characterized as oxygen based free chemical particles, if present in excess, causes contractile dysfunction and structural damage in the myocardium [5]. ROS production and removal of excess ROS are essential in maintaining the redox state and, homeostasis balance in the cell [6]. ROS mediated oxidative damage in cardiomyocytes is responsible for structural integrity of the myocardium. The mechanism by which Tb4 modulates cardiac protection under oxidative stress is not known. The purpose of this study is to dissect the cardioprotective mechanism of Tb4 on H2O2 induced cardiac damage
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