ABSTRACT
AIMS: We 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. CONCLUSIONS: RSV enhances cardiac SDF-1 excretion after AMI partially through a SIRT1 normalization/p53 inactivation pathway.
Subject(s)
Chemokine CXCL12/metabolism , Myocardial Infarction/metabolism , Myocardium/metabolism , Stilbenes/pharmacology , Tumor Suppressor Protein p53/metabolism , Up-Regulation/drug effects , Acetylation/drug effects , Animals , Cell Hypoxia/drug effects , Fibrosis , Gene Silencing/drug effects , Heart Function Tests/drug effects , Heart Ventricles/drug effects , Heart Ventricles/metabolism , Heart Ventricles/pathology , Heart Ventricles/physiopathology , Male , Mice , Mice, Inbred C57BL , Myocardial Infarction/diagnostic imaging , Myocardial Infarction/pathology , Myocardial Infarction/physiopathology , Myocardium/pathology , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Resveratrol , Sirtuin 1/metabolism , UltrasonographyABSTRACT
To reveal the involvement of oxidative stress in hypertension and insulin resistance. Angiotensin Ⅱ was given to adrenomedullin-knockout mice for 4 weeks. 4-Hydroxy-TEMPOL, a superoxide scavenger mimetic was also employed. The results suggested that adrenomedullin may exert a protective effect against insulin resistance via its intrinsic antioxidant effect.
