Deficiency of proline/serine-rich coiled-coil protein 1 (PSRC1) accelerates trimethylamine N-oxide-induced atherosclerosis in ApoE−/− mice

Jun 11, 2022Journal of molecular and cellular cardiology

Lack of PSRC1 protein speeds up artery disease caused by trimethylamine N-oxide in mice without ApoE

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Abstract

Plasma TMAO levels were increased and negatively associated with decreased PSRC1 in patients with coronary artery disease.

TMAO is linked to atherosclerosis and may contribute to coronary artery disease beyond controlled LDL-C levels.
Increased TMAO levels correlate with reduced PSRC1 expression in blood cells from patients with atherosclerosis.
Animal studies showed that TMAO inhibits PSRC1 expression through DNA changes, leading to accelerated atherosclerosis.
PSRC1 deficiency in animals resulted in greater atherogenesis, marked by more macrophage infiltration and inflammation.
Overexpression of PSRC1 in macrophages mitigated cholesterol accumulation and inflammation triggered by TMAO.

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AIMS: The main therapeutic strategies for coronary artery disease (CAD) are mainly based on the correction of abnormal cholesterol levels; however, residual risks remain. The newly proven gut microbial metabolite trimethylamine N-oxide (TMAO) linked with CAD has broadened our horizons. In this study, we determined the role of proline/serine-rich coiled-coil protein 1 (PSRC1) in TMAO-driven atherosclerosis.

METHODS AND RESULTS: We first analyzed the levels of TMAO and PSRC1 in patients with or without atherosclerosis with a target LDL-C < 1.8 mmol/L. Plasma TMAO levels were increased and negatively associated with decreased PSRC1 in peripheral blood mononuclear cells. Animals and in vitro studies showed that TMAO inhibited macrophage PSRC1 expression due to DNA hypermethylation of CpG islands. ApoEmice fed a choline-supplemented diet exhibited reduced PSRC1 expression accompanied by increased atherosclerotic lesions and plasma TMAO levels. We further deleted PSRC1 in apoEmice and PSRC1 deficiency significantly accelerated choline-induced atherogenesis, characterized by increased macrophage infiltration, foam cell formation and M1 macrophage polarization. Mechanistically, we overexpressed and knocked out PSRC1 in cultured macrophages to explore the mechanisms underlying TMAO-induced cholesterol accumulation and inflammation. PSRC1 deletion impaired reverse cholesterol transport and enhanced cholesterol uptake and inflammation, while PSRC1 overexpression rescued the proatherogenic phenotype observed in TMAO-stimulated macrophages, which was partially attributed to sulfotransferase 2B1b (SULT2B1b) inhibition. -/--/-

CONCLUSIONS: Herein, clinical data provide evidence that TMAO may participate in the development of CAD beyond well-controlled LDL-C levels. Our work also suggests that PSRC1 is a negative regulator mediating the unfavorable effects of TMAO-containing diets. Therefore, PSRC1 overexpression and reduced choline consumption may further alleviate atherosclerosis.

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Deficiency of proline/serine-rich coiled-coil protein 1 (PSRC1) accelerates trimethylamine N-oxide-induced atherosclerosis in ApoE−/− mice

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