c-Kit suppresses atherosclerosis in hyperlipidemic mice.
c-Kit suppresses atherosclerosis in hyperlipidemic mice.
复制标题
c-Kit 抑制高脂血症小鼠的动脉粥样硬化。
DOI：
10.1152/ajpheart.00062.2019
复制
发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Vazquez-Padron,RobertoI
中科院分区：
文献类型：
--
作者：
Song,Lei;Zigmond,ZacharyM;Martinez,Laisel;Lassance-Soares,RobertaM;Macias,AlejandroE;Velazquez,OmaidaC;Liu,Zhao-Jun;Salama,Alghidak;Webster,KeithA;Vazquez-Padron,RobertoI
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 & NOTEWORTHYThis study describes the novel vasculoprotective role of c-Kit against atherosclerosis and its function in the preservation of the SMC contractile phenotype.
