HDAC inhibitor valproic acid protects heart function through Foxm1 pathway after acute myocardial infarction.

Shuo Tian,Todd J Herron,Shaoxiang Xian,Liu Liu,Peter X Ma,Yongqing Li,Hasan B Alam,Ienglam Lei,Zhong Wang,Yijing Guo,Wenbin Gao,Y Eugene Chen,Jeffery Creech

doi:10.1016/j.ebiom.2018.12.003

Abstract

BackgroundEpigenetic histone acetylation is a major event controlling cell functions, such as metabolism, differentiation and repair. Here, we aim to determine whether Valproic acid (VPA), a FDA approved inhibitor of histone deacetylation for bipolar disease, could protect heart against myocardial infarction (MI) injury and elucidate key molecular pathways.MethodsVPA was administrated to MI rats at different time points, onset and after MI injury. Echocardiography, histology, serum biology assays, and gene expression, inhibition, and over-expression were performed to characterize the systolic function, infarct size, gene and signaling pathways.FindingsVPA treatment reduced the infarct size by ~50% and preserved the systolic function of heart after acute MI in rats. Even 60 min after infarction, VPA treatment significantly decreased infarct size. Furthermore, long-term treatment of VPA markedly improved myocardial performance. VPA regulated gene expression essential for cell survival and anti-inflammatory response. Consequently, oxidative stress and cell death were notably reduced after VPA treatment. Moreover, Foxm1 was identified as a potential key target of VPA. Overexpression of Foxm1 provided similar heart protective effect to VPA treatment. Particularly, both VPA treatment and Foxm1 over-expression repressed inflammatory response after MI for heart protection. In contrast, inhibition of Foxm1 activity abolished the cardiac protective effect of VPA. VPA mediated CM protection through Foxm1 upregulation was also identified in a human ESC derived CM hypoxia/reperfusion system.InterpretationVPA treatments significantly reduce cardiac damage after MI and the cardioprotective effect of VPA is likely mediated via Foxm1 pathway.FundThis work was mainly supported by 1R01HL109054.

Highlights

Cardiovascular disease (CVD) is the leading cause of death in the world [1]
We show that Class I histone deacetylases (HDAC) inhibitor Valproic acid (VPA) exerts prominent cardio-protective role after myocardial infarction (MI), which is characterized by significant reduction of infarct size, cell death, circulation markers, and cardiac remodeling with enhanced cardiac function
We show that VPA treatment increases the cardiomyocyte metabolic expression program after MI and suppresses the inflammation response

Summary

Introduction

Cardiovascular disease (CVD) is the leading cause of death in the world [1]. In particular, myocardial infarction (MI), commonly known as heart attack, results in permanent heart muscle damage or death, and is the number one killer of heart patients. Device-based, and do not address the underlying problem of CM loss These treatments cannot regenerate the myocardium and rescue the injured ventricle [2]. These statistics underscore the critical need for developing effective therapeutic strategies to preserve the pumping function after heart attack. We aim to determine whether Valproic acid (VPA), a FDA approved inhibitor of histone deacetylation for bipolar disease, could protect heart against myocardial infarction (MI) injury and elucidate key molecular pathways. Findings: VPA treatment reduced the infarct size by ~50% and preserved the systolic function of heart after acute MI in rats. Overexpression of Foxm provided similar heart protective effect to VPA treatment. Interpretation: VPA treatments significantly reduce cardiac damage after MI and the cardioprotective effect of VPA is likely mediated via Foxm pathway.

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