PMID- 31441677 OWN - NLM STAT- MEDLINE DCOM- 20200406 LR - 20231213 IS - 1522-1539 (Electronic) IS - 0363-6135 (Print) IS - 0363-6135 (Linking) VI - 317 IP - 4 DP - 2019 Oct 1 TI - c-Kit suppresses atherosclerosis in hyperlipidemic mice. PG - H867-H876 LID - 10.1152/ajpheart.00062.2019 [doi] AB - 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, SM22alpha) 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. FAU - Song, Lei AU - Song L AD - Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, Florida. FAU - Zigmond, Zachary M AU - Zigmond ZM AD - Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, Florida. FAU - Martinez, Laisel AU - Martinez L AD - Department of Surgery, University of Miami, Miller School of Medicine, Miami, Florida. FAU - Lassance-Soares, Roberta M AU - Lassance-Soares RM AD - Department of Surgery, University of Miami, Miller School of Medicine, Miami, Florida. FAU - Macias, Alejandro E AU - Macias AE AUID- ORCID: 0000-0001-6863-5457 AD - Department of Surgery, University of Miami, Miller School of Medicine, Miami, Florida. FAU - Velazquez, Omaida C AU - Velazquez OC AD - Department of Surgery, University of Miami, Miller School of Medicine, Miami, Florida. FAU - Liu, Zhao-Jun AU - Liu ZJ AD - Department of Surgery, University of Miami, Miller School of Medicine, Miami, Florida. FAU - Salama, Alghidak AU - Salama A AD - Department of Surgery, University of Miami, Miller School of Medicine, Miami, Florida. FAU - Webster, Keith A AU - Webster KA AD - Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, Florida. FAU - Vazquez-Padron, Roberto I AU - Vazquez-Padron RI AD - Department of Molecular and Cellular Pharmacology, University of Miami, Miller School of Medicine, Miami, Florida. AD - Department of Surgery, University of Miami, Miller School of Medicine, Miami, Florida. LA - eng GR - R01 HL109582/HL/NHLBI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20190823 PL - United States TA - Am J Physiol Heart Circ Physiol JT - American journal of physiology. Heart and circulatory physiology JID - 100901228 RN - 0 (ABCG1 protein, mouse) RN - 0 (ATP Binding Cassette Transporter, Subfamily G, Member 1) RN - 0 (Calcium-Binding Proteins) RN - 0 (Kit protein, mouse) RN - 0 (Microfilament Proteins) RN - 0 (Muscle Proteins) RN - 0 (transgelin) RN - EC 2.7.10.1 (KIT protein, human) RN - EC 2.7.10.1 (Proto-Oncogene Proteins c-kit) SB - IM MH - ATP Binding Cassette Transporter, Subfamily G, Member 1/genetics/metabolism MH - Animals MH - Aorta/metabolism/ultrastructure MH - Aortic Diseases/etiology/metabolism/pathology/*prevention & control MH - Atherosclerosis/etiology/metabolism/pathology/*prevention & control MH - Calcium-Binding Proteins/genetics/metabolism MH - Cells, Cultured MH - Disease Models, Animal MH - Foam Cells/metabolism/pathology MH - Humans MH - Hyperlipidemias/*complications/metabolism MH - Mice, Knockout, ApoE MH - Microfilament Proteins/genetics/metabolism MH - Muscle Proteins/genetics/metabolism MH - Muscle, Smooth, Vascular/*metabolism/ultrastructure MH - Mutation MH - Myocytes, Smooth Muscle/*metabolism/ultrastructure MH - Phenotype MH - Plaque, Atherosclerotic MH - Promoter Regions, Genetic MH - Proto-Oncogene Proteins c-kit/genetics/*metabolism MH - Signal Transduction MH - Calponins PMC - PMC6843012 OTO - NOTNLM OT - atheroma OT - atherosclerosis OT - c-Kit OT - mouse OT - phenotypic switch OT - smooth muscle cell COIS- No conflicts of interest, financial or otherwise, are declared by the authors. EDAT- 2019/08/24 06:00 MHDA- 2020/04/09 06:00 PMCR- 2020/10/01 CRDT- 2019/08/24 06:00 PHST- 2019/08/24 06:00 [pubmed] PHST- 2020/04/09 06:00 [medline] PHST- 2019/08/24 06:00 [entrez] PHST- 2020/10/01 00:00 [pmc-release] AID - H-00062-2019 [pii] AID - 10.1152/ajpheart.00062.2019 [doi] PST - ppublish SO - Am J Physiol Heart Circ Physiol. 2019 Oct 1;317(4):H867-H876. doi: 10.1152/ajpheart.00062.2019. Epub 2019 Aug 23.