Background: We formerly demonstrated that cardiomyocyte Kr?ppel-like factor (KLF) 5 regulates cardiac essential fatty acid oxidation. As heart failure continues to be connected with altered essential fatty acid oxidation, we investigated the function of cardiomyocyte KLF5 in fat metabolic process and pathophysiology of ischemic heart failure.

Methods: Using real-time polymerase squence of events and Western blot, we investigated the KLF5 expression alterations in a myocardial infarction (MI) mouse model and heart tissue from patients with ischemic heart failure. Using 2D echocardiography, we evaluated the result of KLF5 inhibition after MI using medicinal KLF5 inhibitor ML264 and rodents with cardiomyocyte-specific KLF5 deletion (αMHC [α-myosin heavy chain]-KLF5-/-). We identified the participation of KLF5 in controlling fat metabolic process and ceramide accumulation after MI using liquid chromatography-tandem mass spectrometry, and Western blot and real-time polymerase squence of events analysis of ceramide metabolic process-related genes. We lastly evaluated the result of cardiomyocyte-specific KLF5 overexpression (αMHC-rtTA [reverse tetracycline-controlled transactivator]-KLF5) on cardiac function and ceramide metabolic process, and saved the phenotype using myriocin to hinder ceramide biosynthesis.

Results: KLF5 mRNA and protein levels were greater in human ischemic heart failure samples as well as in rodent models at 24 hrs, 2 days, and 4 days publish-permanent left heart ligation. αMHC-KLF5-/- rodents and rodents given ML264 had greater ejection fraction minimizing ventricular volume and heart weight after MI. Lipidomic analysis demonstrated that αMHC-KLF5-/- rodents with MI had lower myocardial ceramide levels in contrast to littermate control rodents with MI, although basal ceramide content of αMHC-KLF5-/- rodents wasn’t different in charge rodents. KLF5 ablation covered up the expression of SPTLC1 and SPTLC2 (serine palmitoyltransferase [SPT] lengthy-chain base subunit ()1 2, correspondingly), which regulate de novo ceramide biosynthesis. We confirmed our previous findings that myocardial SPTLC1 and SPTLC2 levels are elevated in heart failure patients. Consistently, αMHC-rtTA-KLF5 rodents demonstrated elevated SPTLC1 and SPTLC2 expression, greater myocardial ceramide levels, and systolic disorder beginning 2 days after KLF5 induction. Management of αMHC-rtTA-KLF5 rodents with myriocin that inhibits SPT, covered up myocardial ceramide levels and alleviated systolic disorder.

Conclusions: KLF5 is caused during the introduction of ischemic heart failure in humans and rodents and stimulates ceramide biosynthesis. Genetic or medicinal inhibition of KLF5 in rodents with MI prevents ceramide accumulation, alleviates eccentric remodeling, and increases ejection fraction. Thus, KLF5 emerges like a novel therapeutic target to treat ischemic heart failure.

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