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Role of cardiomyocyte KLF5 in heart failure

心肌细胞KLF5在心力衰竭中的作用

基本信息

批准号：
10666690
负责人：
Konstantinos Drosatos
金额：
$ 46.73万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10666690
关键词：
Ablation Address Affect Anabolism Binding Blood C57BL/6 Mouse Cardiac Cardiac Myocytes Cardiomyopathies Cardiotoxicity Catabolism Ceramides Chronic Disease Doxycycline Enzymes Family Family member Fibrosis Functional disorder Gene Expression Heart Heart failure Histologic Human Intervention Kruppel-like transcription factors Mediating Metabolic Metabolism MicroRNAs Mus Myocardial Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Organ Oxidative Stress Oxygen PPAR alpha Pathology Pathway interactions Patients Persons Porifera Prognosis Protein Inhibition Proteins Pump Quantitative Reverse Transcriptase PCR RNA Role Sampling Structure Therapeutic Time Up-Regulation design effective therapy heart function heart metabolism implantation improved inhibitor interest ischemic cardiomyopathy left ventricular assist device lipidomics member mouse model pharmacologic promoter protein expression response screening serine palmitoyltransferase therapeutic target thermozymocidin

项目摘要

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.

摘要