Abstract
<p>Rationale: Increased receptor tyrosine kinase (RTK) activity has been historically linked to atherosclerosis. At the beginning of my studies, I found the RTK c-Kit is present within atherosclerotic plaques of both humans and mice, and the global deficiency in c-Kit function increased atherosclerosis in hyperlipidemic mice.</p>
<p>Objective: This study aimed to investigate if such unusual atheroprotective phenotype depends upon c-Kit’s function in smooth muscle cells (SMC). </p>
<p>Results: c-Kit was detected in human and mouse healthy and atherosclerotic aortas. The loss of c-Kit function in mutant c-Kit (KitW/Wv) mice caused a significant decrease in vasorelaxation and increase in blood pressure due to a significant loss of sGC in vascular smooth muscle cells. Further, hyperlipidemic mutant mice (KitW/Wv ApoE-/-) showed a significant increase in atherosclerotic burden and necrotic core size compared to wild type controls. Moreover, SMC specific KO of c-Kit in hyperlipidemic mice (KitSMC ApoE-/-) significantly increased atherosclerosis, plaque size and necrotic core area in the aortic sinus of hyperlipidemic mice. This protective effect was further studied in c-Kit KO SMC tracing mice (KitSMC eYFP) that labeled SMCs after TAM injection. The c-Kit KO SMCs were more prone to migrate, proliferate, and express foam cell markers (e.g., Mac2 and MCAM) than those from control littermate animals. Loss of c-Kit in cultured SMCs led to an increase in synthetic SMC phenotype. RNAseq analysis showed a significant upregulation in genes associated with cell proliferation, migration, lipid metabolism, and inflammation. I detected a significant increase in MCAM protein expression in KitMut SMCs and the aortic sinus of KitSMC hyperlipidemic mice.</p>
<p>Conclusion: We can conclude that c-Kit plays an atheroprotective role in the arterial vasculature by reducing the transcription of genes associated with synthetic SMC transformation and thus preventing their migration, proliferation, and foam cell formation during atherosclerosis.<br />
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