4.6 Article

c-Kit suppresses atherosclerosis in hyperlipidemic mice

Journal

Publisher

AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00062.2019

Keywords

atheroma; atherosclerosis; c-Kit; mouse; phenotypic switch; smooth muscle cell

Funding

  1. National Heart, Lung, and Blood Institute [R01-HL-109582]

Ask authors/readers for more resources

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 (Kit(Mut)) after they were fed a high-fat diet (HFD) for 16 wk. Kit(Mut) mice demonstrated substantially greater atherosclerosis compared with control (Kit(WT)) littermates (P < 0.01). Transplantation of c-Kit-positive bone marrow cells into Kit(Mut) mice 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, SM22 alpha) 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 Kit(Mut) SMCs 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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.6
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available