Meteorin-like protein inhibits vascular smooth muscle cell-derived foam cell formation and atherosclerosis via KIT- endoplasmic reticulum stress signaling

Abstract

Objective

Vascular smooth muscle cell (VSMC)-derived foam cell formation is a major contributor to atherosclerosis progression and plaque instability. Meteorin-like protein (METRNL), a secreted organokine with known metabolic and anti-inflammatory effects, has been linked to cardiovascular protection, but its role in atherosclerosis is not well defined. This study investigated the function of METRNL in VSMC-derived foam cell formation and atherosclerosis and explored the underlying signaling mechanisms.

Methods

ApoE^−/− mice were used to investigate the role of METRNL in atherosclerosis. VSMC-derived foam cell formation was evaluated in human VSMC treated with oxidized LDL with or without METRNL supplementation.

Results

METRNL levels declined during atherosclerosis progression and were restored during regression. METRNL selectively inhibited foam cell formation in VSMCs—but not in macrophages—by downregulating CD36-mediated cholesterol uptake and suppressing endoplasmic reticulum stress through KIT signaling. Deletion of KIT specifically in smooth muscle cells abolished these protective effects. The transcription factor SP1 was found to bind directly to the METRNL promoter and enhance its expression. Clinically, lower serum METRNL levels were independently associated with increased risk and severity of acute coronary syndrome.

Conclusion

METRNL protects against VSMC foam cell formation and atherosclerosis by enhancing KIT signaling, thereby reducing ER stress and subsequent cholesterol uptake. These findings position METRNL as a potential therapeutic target and biomarker for atherosclerotic cardiovascular disease.