Krüppel-like factor 14 deletion in myeloid cells accelerates atherosclerotic lesion development

Author:

Wang Huilun1ORCID,Guo Yanhong2,Lu Haocheng2ORCID,Luo Yonghong23ORCID,Hu Wenting2,Liang Wenying1ORCID,Garcia-Barrio Minerva T2ORCID,Chang Lin2,Schwendeman Anna4ORCID,Zhang Jifeng2ORCID,Chen Y Eugene12ORCID

Affiliation:

1. Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA

2. Department of Internal Medicine, Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, MI 48109, USA

3. Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China

4. Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, MI 48109, USA

Abstract

Abstract Aims Atherosclerosis is the dominant pathologic basis of many cardiovascular diseases. Large genome-wide association studies have identified that single-nucleotide polymorphisms proximal to Krüppel-like factor 14 (KLF14), a member of the zinc finger family of transcription factors, are associated with higher cardiovascular risks. Macrophage dysfunction contributes to atherosclerosis development and has been recognized as a potential therapeutic target for treating many cardiovascular diseases. Herein, we address the biologic function of KLF14 in macrophages and its role during the development of atherosclerosis. Methods and results KLF14 expression was markedly decreased in cholesterol loaded foam cells, and overexpression of KLF14 significantly increased cholesterol efflux and inhibited the inflammatory response in macrophages. We generated myeloid cell-selective Klf14 knockout (Klf14LysM) mice in the ApoE-/- background for the atherosclerosis study. Klf14LysMApoE-/- and litter-mate control mice (Klf14fl/flApoE-/-) were placed on the Western Diet for 12 weeks to induce atherosclerosis. Macrophage Klf14 deficiency resulted in increased atherosclerosis development without affecting the plasma lipid profiles. Klf14-deficient peritoneal macrophages showed significantly reduced cholesterol efflux resulting in increased lipid accumulation and exacerbated inflammatory response. Mechanistically, KLF14 upregulates the expression of a key cholesterol efflux transporter, ABCA1 (ATP-binding cassette transporter A1), while it suppresses the expression of several critical components of the inflammatory cascade. In macrophages, activation of KLF14 by its activator, perhexiline, a drug clinically used to treat angina, significantly inhibited the inflammatory response and increased cholesterol efflux in a KLF14-dependent manner in macrophages without triggering hepatic lipogenesis. Conclusions This study provides insights into the anti-atherosclerotic effects of myeloid KLF14 through promoting cholesterol efflux and suppressing the inflammatory response. Activation of KLF14 may represent a potential new therapeutic approach to prevent or treat atherosclerosis.

Funder

National Institutes of Health

American Heart Association

Publisher

Oxford University Press (OUP)

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

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