Role of cardiomyocyte KLF5 in heart failure

摘要 心肌缺血(MI)会导致心脏重构和心力衰竭(HF)。多个机制和 细胞通路影响疾病的病理生理，因此对有效识别提出了挑战 治疗。我们在晚期心力衰竭患者和小鼠缺血心肌标本中的初步发现 心脏和心肌细胞提示转录因子Krüppel样因子5(KLF5)是一种中心成分 缺血型心力衰竭。具体地说，我们认为KLF5调控神经酰胺的生物合成和miR30的表达， 两者都与心力衰竭预后较差有关。基于我们之前的研究，该研究表明 KLF5调节心脏代谢，其他研究表明心脏代谢在 不同类型的心肌病，我们评估了KLF5表达的改变是否可能参与了不利的 心脏重塑。我们在人类心肌样本和各种小鼠模型中显示MI增加 KLF5的表达，最终刺激丝氨酸棕榈酰转移酶和神经酰胺的生物合成，AS 同时抑制所有miR30基因的表达。另一方面，对KLF5的抑制是保护性的。 根据这些发现，我们假设抑制KLF5将通过抑制KLF5的抑制而减轻缺血性心力衰竭。 神经酰胺合成及miR30表达上调。为了解决我们的假设，我们设计了 以下是具体目标： 目的1：探讨KLF5调节心脏神经酰胺代谢的机制。 会导致心脏功能不全。 目的2：阐明miR30抑制在介导心脏毒性作用中的作用 MI中的KLF5。 目的3：探讨KLF5抑制剂对心力衰竭的治疗潜力 拟议的研究将首次将KLF5确定为心脏病理生理学的中心组成部分 并将表明KLF5抑制可作为治疗缺血性心力衰竭的潜在靶点。

ABSTRACT Myocardial ischemia (MI) leads to cardiac remodeling and heart failure (HF). Multiple mechanisms and cellular pathways affect pathophysiology of the disease and therefore challenge identification of effective treatments. Our preliminary findings in human myocardial samples of advanced HF and mouse ischemic hearts and cardiomyocytes suggest transcriptional factor Krüppel-like factor 5 (KLF5) as a central component of ischemic HF. Specifically, we propose that KLF5 regulates ceramide biosynthesis and miR30 expression, both of which have been associated with worse prognosis in HF. Based on our previous study, which showed that KLF5 regulates cardiac metabolism and other studies showing that cardiac metabolism is altered in various types of cardiomyopathy, we assessed whether altered KLF5 expression may be involved in adverse cardiac remodeling. We showed in human myocardial samples and various mouse models that MI increased KLF5 expression, which eventually stimulates serine palmitoyl-transferase and biosynthesis of ceramides, as well as it suppresses expression of all miR30s. On the other hand, suppression of KLF5 was protective.Based on these findings, we hypothesize that KLF5 inhibition will alleviate ischemic HF via suppression of ceramide synthesis and upregulation of miR30 expression. To address our hypothesis, we have designed the following Specific Aims: Aim 1: Investigate the mechanism via which KLF5 regulates cardiac ceramide metabolism and causes cardiac dysfunction. Aim 2: Elucidate the involvement of miR30 suppression in mediating the cardiotoxic effect of KLF5 in MI. Aim 3: Explore the therapeutic potential of KLF5 inhibition in HF The proposed study will identify for the first time KLF5 as a central component of cardiac pathophysiology in MI and will indicate KLF5 suppression as a potential therapeutic target for ischemic HF.