c-Kit suppresses atherosclerosis in hyperlipidemic mice

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Atherosclerosis Research

Background:

• Atherosclerosis is a leading cause of global mortality.
• c-Kit (CD117), a receptor tyrosine kinase, is present in arterial cells, but its role in cardiovascular disease is unknown.
• Understanding c-Kit's function is crucial for developing new atherosclerosis therapies.

Purpose of the Study:

• To investigate the role of c-Kit in the development of atherosclerosis.
• To elucidate the underlying mechanisms by which c-Kit influences vascular smooth muscle cells (SMCs) in the context of atherosclerosis.

Main Methods:

• Quantification of atherosclerotic plaques in c-Kit-deficient (Kit^Mut) and wild-type (Kit^WT) mice on a high-fat diet.
• Analysis of SMC organization, morphology, and phenotype markers via histopathology and electron microscopy.
• Assessment of lipid accumulation and ATP-binding cassette transporter G1 (ABCG1) expression in SMCs.
• In vitro studies involving reconstitution of c-Kit in cultured Kit^Mut SMCs.

Main Results:

• c-Kit deficiency significantly exacerbated atherosclerosis in mice fed a high-fat diet.
• Reduced arterial c-Kit, not bone marrow-derived c-Kit, was associated with increased atherosclerosis.
• Absence of c-Kit led to disorganized, vacuolated SMCs, downregulated contractile markers (calponin, SM22α), increased lipid accumulation, and reduced ABCG1 expression.
• Restoring c-Kit in mutant SMCs normalized morphology, reduced proliferation, and restored contractile markers.

Conclusions:

• c-Kit plays a novel vasculoprotective role in preventing atherosclerosis.
• c-Kit is essential for preserving the contractile phenotype of vascular smooth muscle cells.
• Targeting c-Kit may offer a therapeutic strategy for atherosclerosis.