Introduction:
Our lab previously showed that cardiomyocyte Krüppel-like factor (KLF)-5 regulates cardiac fatty acid oxidation. Various studies have associated heart failure with altered cardiac fatty acid oxidation and lipotoxicity.
Hypothesis:
Aberrant regulation of KLF5 contributes to pathophysiology and metabolic perturbations in ischemic heart failure.
Methods and Results:
Analysis of KLF5 mRNA and protein levels in human ischemic heart failure samples and in rodent models 2- and 4-weeks post-myocardial infarction (MI) showed significantly increased KLF5 expression. To investigate the involvement of KLF5 in the pathophysiology of ischemic heart failure, we treated mice that were subjected to MI with a pharmacological KLF5 inhibitor (ML264). ML264 increased ejection fraction and reduced diastolic volume. Likewise, mice with cardiomyocyte-specific KLF5 deletion (αMHC-KLF5
-/-
mice) were protected from ischemic heart failure. Lipidomic analysis by LC-MS/MS showed that αMHC-KLF5
-/-
mice after MI had lower myocardial ceramide levels compared with control mice with MI. Accordingly, the expression of cardiac SPTLC1 and SPTLC2, which regulate de novo ceramide biosynthesis, was higher in control mice with MI and lower in αMHC-KLF5
-/-
mice with MI. KLF5 overexpression in HL1 cardiomyocytes increased SPTLC1 and SPTLC2 mRNA and protein levels. ChIP-qPCR and luciferase promoter assays showed that KLF5 activates the promoters of these genes via direct binding. To assess the transcriptional effects of KLF5 independent from other changes that occur with MI, we generated a mouse model of inducible (Dox-ON), cardiomyocyte-specific expression of KLF5 (αMHC-rtTA-KLF5). Systolic dysfunction was evident 2-weeks following KLF5 induction. Heart tissue from these mice exhibited increased SPTLC1 and SPTLC2 mRNA and protein levels, and inhibition of SPT using myriocin suppressed myocardial ceramide levels and alleviated systolic dysfunction.
Conclusions:
KLF5 is induced during the development of ischemic heart failure in humans and mice, and stimulates expression of SPTLC1 and SPTLC2 that promote ceramide biosynthesis. KLF5 inhibition emerges as a novel therapeutic target to protect against ischemic heart failure.
Malonyl Coenzyme A Decarboxylase Inhibition Protects the Ischemic Heart by Inhibiting Fatty Acid Oxidation and Stimulating Glucose Oxidation
