c-Kit suppresses atherosclerosis in hyperlipidemic mice

Author:

Song Lei1,Zigmond Zachary M.1,Martinez Laisel2,Lassance-Soares Roberta M.2,Macias Alejandro E.2ORCID,Velazquez Omaida C.2,Liu Zhao-Jun2,Salama Alghidak2,Webster Keith A.1,Vazquez-Padron Roberto I.12

Affiliation:

1. Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, Florida

2. Department of Surgery, University of Miami, Miller School of Medicine, Miami, Florida

Abstract

Atherosclerosis is the most common underlying cause of cardiovascular morbidity and mortality worldwide. c-Kit (CD117) is a member of the receptor tyrosine kinase family, which regulates differentiation, proliferation, and survival of multiple cell types. Recent studies have shown that c-Kit and its ligand stem cell factor (SCF) are present in arterial endothelial cells and smooth muscle cells (SMCs). The role of c-Kit in cardiovascular disease remains unclear. The aim of the current study is to determine the role of c-Kit in atherogenesis. For this purpose, atherosclerotic plaques were quantified in c-Kit-deficient mice (KitMut) after they were fed a high-fat diet (HFD) for 16 wk. KitMutmice demonstrated substantially greater atherosclerosis compared with control (KitWT) littermates ( P < 0.01). Transplantation of c-Kit-positive bone marrow cells into KitMutmice failed to rescue the atherogenic phenotype, an indication that increased atherosclerosis was associated with reduced arterial c-Kit. To investigate the mechanism, SMC organization and morphology were analyzed in the aorta by histopathology and electron microscopy. SMCs were more abundant, disorganized, and vacuolated in aortas of c-Kit mutant mice compared with controls ( P < 0.05). Markers of the “contractile” SMC phenotype (calponin, SM22α) were downregulated with pharmacological and genetic c-Kit inhibition ( P < 0.05). The absence of c-Kit increased lipid accumulation and significantly reduced the expression of the ATP-binding cassette transporter G1 (ABCG1) necessary for lipid efflux in SMCs. Reconstitution of c-Kit in cultured KitMutSMCs resulted in increased spindle-shaped morphology, reduced proliferation, and elevated levels of contractile markers, all indicators of their restored contractile phenotype ( P < 0.05).NEW & NOTEWORTHY This study describes the novel vasculoprotective role of c-Kit against atherosclerosis and its function in the preservation of the SMC contractile phenotype.

Publisher

American Physiological Society

Subject

Physiology (medical),Cardiology and Cardiovascular Medicine,Physiology

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