Rogers Russell G, Otis Jeffrey S
Muscle Biology Laboratory, Department of Kinesiology and Health, Georgia State University, Atlanta, GA, 30302, USA.
Cedars-Sinai Heart Institute, 8700 Beverly Boulevard, Los Angeles, CA, 90048, USA.
Cardiovasc Drugs Ther. 2017 Feb;31(1):29-38. doi: 10.1007/s10557-016-6707-9.
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.
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.
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.
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.
心肌梗死会导致生理紊乱，进而引起心肌的结构和功能改变。此外，氧化应激会加剧心脏重塑并推动疾病进展。遗憾的是，尽管动物研究报告了阳性结果，但抗氧化剂在临床试验中的治疗并未显示出任何益处，这值得进一步研究其作用机制。因此，本研究的目的是阐明抗氧化剂白藜芦醇在治疗缺血性心脏病方面一种此前未知的作用机制。
雄性Sprague-Dawley大鼠接受为期四周的慢性心肌缺血，部分大鼠每日接受白藜芦醇治疗（10毫克/千克/天）。分别通过免疫印迹和定量PCR分析来确定Krüppel样因子15（KLF15）的表达和信号传导。
慢性心肌缺血降低了KLF15的蛋白表达。与此同时，在未经治疗的心脏中，积极参与心脏重塑的KLF15基因靶点的mRNA转录本显著增加。重要的是，每日给予白藜芦醇治疗可刺激KLF15表达，这与基因表达减弱和心脏表型改善相关。此外，我们描述了KLF15在氧化还原稳态调节中的新作用。
基于我们目前的研究结果，白藜芦醇治疗似乎可诱导KLF15表达，这可能部分解释了其改善缺血性损伤后心脏表型的治疗效果。
