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.