Cardiac Myocyte KLF5 Regulates Ppara Expression and Cardiac Function

Overview

Journal Circ Res

Specialty Cardiology & Vascular Diseases

Date 2015 Nov 18

PMID 26574507

Citations 70

Authors

Konstantinos Drosatos

Nina M Pollak

Christine J Pol

Panagiotis Ntziachristos

Florian Willecke

Mesele-Christina Valenti

Chad M Trent

Yunying Hu

Shaodong Guo

Iannis Aifantis

Ira J Goldberg

Affiliations

Soon will be listed here.

Abstract

Rationale: Fatty acid oxidation is transcriptionally regulated by peroxisome proliferator-activated receptor (PPAR)α and under normal conditions accounts for 70% of cardiac ATP content. Reduced Ppara expression during sepsis and heart failure leads to reduced fatty acid oxidation and myocardial energy deficiency. Many of the transcriptional regulators of Ppara are unknown.

Objective: To determine the role of Krüppel-like factor 5 (KLF5) in transcriptional regulation of Ppara.

Methods And Results: We discovered that KLF5 activates Ppara gene expression via direct promoter binding. This is blocked in hearts of septic mice by c-Jun, which binds an overlapping site on the Ppara promoter and reduces transcription. We generated cardiac myocyte-specific Klf5 knockout mice that showed reduced expression of cardiac Ppara and its downstream fatty acid metabolism-related targets. These changes were associated with reduced cardiac fatty acid oxidation, ATP levels, increased triglyceride accumulation, and cardiac dysfunction. Diabetic mice showed parallel changes in cardiac Klf5 and Ppara expression levels.

Conclusions: Cardiac myocyte KLF5 is a transcriptional regulator of Ppara and cardiac energetics.

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