Pharmacological inhibition of TRPM4 channel stabilizes atherosclerotic plaque via inhibiting AMPK-Beclin1-mediated autophagy.

Transient receptor potential melastatin 4 (TRPM4) channel plays an important role in regulation of endothelial dysfunction. However, whether TRPM4 contributes to the developing of atherogenesis remains unexplored. In this study, ApoE-/- mice feeding with a high-fat diet (HFD) for 16 weeks to establish atherosclerosis model, were administered with or without 9-phenanthrol (9-Phe), a specific inhibitor of TRPM4. Our data showed that TRPM4 expression levels in aortas, particularly on endothelium, were significantly increased in HFD-induced atherosclerotic mice. While pharmacological inhibition with 9-Phe failed to reduce the HFD-induced atherosclerotic plaque area, it significantly stabilized vulnerable plaques in HFD-fed ApoE-/- mice. Upon exposed to oxidized low-density lipoprotein (ox-LDL), TRPM4 expression level was notably upregulated in primary cultured endothelial cells (ECs). Both 9-Phe and knockdown of TRPM4 protected ox-LDL-induced impairment of cell viability. Furthermore, ox-LDL-treated ECs showed impaired migration ability and enhanced release of adhesion molecules, including ICAM-1, VCAM-1 and E-selectin, which was also alleviated by 9-Phe. Notably, 9-Phe also inhibited the ox-LDL-triggered autophagy and apoptosis in ECs. Mechanistically, ox-LDL upregulated TRPM4 expression and induced activation of AMPK and autophagy signaling pathway; AMPK agonist acadesine (AICAR) was able to abolish the protective effect of 9-Phe against excessive autophagy and apoptosis in ECs. Taken together, our study reveals that atherosclerotic stress-induced increase in TRPM4 expression may contribute to HFD-induced progression of atherosclerosis and 9-Phe prevents these pathological processes by blunting AMPK-Beclin1-mediated excessive autophagy and apoptosis in ECs. We suggest that TRPM4 may be a potential therapeutic target for preventing HFD-induced atherosclerosis.