Resveratrol Upregulates Cardiac SDF-1 in Mice with Acute Myocardial Infarction through the Deacetylation of Cardiac p53.

Wang Hong,Wang Shou-Dong,Qian Hai-Yan,Jin Chen,Wang Jue,Zhang Qian,Yang Yue-Jin,Shimosawa Tatsuo,Hou Jian-Feng,Meijing Wang

doi:10.1371/journal.pone.0128978

Abstract

AimsWe previously demonstrated that resveratrol (RSV) administration causes cardiac stromal cell-derived factor (SDF)-1 upregulation and can enhance the mobilization of stem cells in mice with acute myocardial infarction (AMI). However, the upstream signal transduction involved in SDF-1 regulation in the setting of AMI and RSV administration remains unclear. Because RSV is a sirtuin 1 (SIRT1) activator and SIRT proteins act as deacetylases, we investigated the role of SIRT1 in SDF-1 upregulation and its subsequent effects.Methods and Results In vitro experiments with H9C2 cardiomyocytes under hypoxia and serum-deprivation conditions showed that p53 acted upstream of SDF-1. RSV could not regulate SDF-1 effectively after SIRT1 silencing, indicating that it is dependent on SIRT1. Subsequently, male C57BL/6 mice were divided into four groups: 1) sham, 2) MI, 3) MI+RSV, and 4) MI+RSV plus nicotinamide, an inhibitor of the deacetylase activity of SIRT (MI+RSV+NAM). Compared with the sham mice, AMI caused a slight increase in the cardiac p53 level and resulted in significant SIRT1 downregulation and p53 acetylation or activation. Compared with the MI mice, MI+RSV administration improved the cardiac SDF-1 level and reversed the reduction of SIRT1 and the activation of p53. Furthermore, we observed less cardiac dysfunction in MI+RSV mice and determined that NAM abolished the effects of RSV.ConclusionsRSV enhances cardiac SDF-1 excretion after AMI partially through a SIRT1 normalization/p53 inactivation pathway.

Highlights

Heart failure develops in a substantial number of patients with acute myocardial infarction (AMI), despite early reperfusion therapy
For the in vivo experiments used to evaluate the effect of SIRT, the mice were randomly divided into four groups: 1) a sham operation group, 2) a myocardial infarction (MI) group, 3) an MI+RSV (25 mg/kg/day in drinking water, from five days before AMI to two days after AMI as described previously [15]) group, and 4) an MI+RSV+nicotinamide (NAM, a SIRT inhibitor, 75 mg/kg/day i.p. by osmotic pump, from five days before AMI to two days after AMI) group
H9C2 cardiomyocytes were transfected with p53 or sirtuin 1 (SIRT1) siRNA, and successful transfection caused a significant downregulation of p53 or SIRT1 (Fig 1A and 1B)

Summary

Introduction

Heart failure develops in a substantial number of patients with acute myocardial infarction (AMI), despite early reperfusion therapy. A higher level of SDF-1 in the injured myocardium improves cardiac repair [2,3,4]. The autologous SDF-1 level peaks 24–72 h after AMI and becomes normalized seven days after AMI [5, 6]. This natural modulation is not sufficient for the induction of functional recovery in many AMI models or patients [5]. SDF-1 delivery by a virus vector, plasmid or direct injection into the injured tissue early after AMI has been proven to be more effective [5, 7, 8], but these methods are not convenient or feasible in clinical therapy. The development of an oral medicine that could be an alternative to these methods may allow a markedly easier and safer application

Methods

Results

Conclusion