Resveratrol-Mediated Expression of KLF15 in the Ischemic Myocardium is Associated with an Improved Cardiac Phenotype

Purpose Myocardial infarction results in physiological derangements that lead to structural and functional alterations to the myocardium. In addition, oxidative stress potentiates cardiac remodeling and drives disease progression. Unfortunately, treatment with antioxidants in clinical trials have failed to show any therapeutic benefits despite the positive results reported in animal studies, which warrants further investigation into their mechanism(s) of action. Accordingly, the aim of this study was to elucidate a previously unknown mechanism of action for the antioxidant, resveratrol, in the treatment of the ischemic heart. Methods Male Sprague-Dawley rats underwent four weeks of chronic myocardial ischemia with or without daily resveratrol treatment (10 mg/kg/day). The expression and signaling of Krüppel-like factor 15 (KLF15) were determined by immunoblot and qPCR analyses, respectively. Results Chronic myocardial ischemia reduced the protein expression of KLF15. In parallel, mRNA transcripts of KLF15 gene targets actively involved in cardiac remodeling were robustly increased in untreated hearts. Importantly, daily treatment with resveratrol stimulated KLF15 expression, which was associated with attenuated gene expression and an improved cardiac phenotype. Additionally, we describe a novel role for KLF15 in the regulation of redox homeostasis. Conclusion Based on our current findings, it appears that resveratrol treatment induces KLF15 expression, which may, in part, explain its therapeutic efficacy to improve the cardiac phenotype following ischemic injury.