Role of cardiomyocyte KLF5 in heart failure

摘要 心肌缺血（MI）导致心脏重构和心力衰竭（HF）。多种机制和 细胞途径影响疾病的病理生理学，因此对有效的 治疗。我们在晚期HF和小鼠缺血性心脏病患者心肌样本中的初步发现 心脏和心肌细胞提示转录因子Krüppel样因子5（KLF5）是一种核心成分， 缺血性心力衰竭具体来说，我们提出KLF5调节神经酰胺的生物合成和miR30的表达， 这两者都与HF的预后不良有关。根据我们之前的研究， KLF5调节心脏代谢，其他研究表明， 在各种类型的心肌病中，我们评估了KLF5表达的改变是否可能参与了心肌病的不良反应。 心脏重塑我们在人类心肌样本和各种小鼠模型中发现， 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， 以及抑制所有miR 30的表达。另一方面，KLF 5的抑制是保护性的。 基于这些发现，我们假设KLF5抑制通过抑制 神经酰胺合成和miR 30表达的上调。为了解决我们的假设，我们设计了 以下具体目标： 目的1：探讨KLF5调节心肌神经酰胺代谢的机制， 会导致心脏功能障碍 目的2：阐明miR30抑制在介导的心脏毒性作用中的作用。 KLF5在MI。 目的3：探索KLF 5抑制剂在HF中的治疗潜力 这项研究将首次确定KLF 5作为心脏病理生理学的核心组成部分 提示KLF5抑制是缺血性HF的潜在治疗靶点。

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.