Pharmacological inhibition of TRPM4 with 9-phenanthrol stabilizes atherosclerotic plaques by blunting AMPK-Beclin1-mediated excessive autophagy and apoptosis in endothelial cells.
TRPM4 expression was significantly upregulated in aortas, particularly on the endothelium, of HFD-induced atherosclerotic ApoE-/- mice.
Pharmacological inhibition of TRPM4 with 9-phenanthrol (9-Phe) failed to reduce HFD-induced atherosclerotic plaque area but significantly stabilized vulnerable plaques in HFD-fed ApoE-/- mice.
Both 9-Phe treatment and TRPM4 knockdown protected endothelial cells from ox-LDL-induced impairment of cell viability.
ox-LDL-treated endothelial cells showed impaired migration ability and enhanced release of adhesion molecules, which was alleviated by 9-Phe.
9-Phe inhibited ox-LDL-triggered autophagy and apoptosis in endothelial cells.
AMPK agonist acadesine (AICAR) abolished the protective effect of 9-Phe against excessive autophagy and apoptosis in endothelial cells.
The study proposes that atherosclerotic stress-induced increase in TRPM4 expression contributes to HFD-induced progression of atherosclerosis via AMPK-Beclin1-mediated excessive autophagy and apoptosis in endothelial cells.
This research suggests that a protein called TRPM4, which forms a channel in cell membranes, plays a previously unexplored role in the development of atherosclerosis (hardening and narrowing of the arteries). The researchers found that TRPM4 levels were elevated in the blood vessel lining (endothelium) of mice fed a high-fat diet, as well as in endothelial cells exposed to oxidized LDL ('bad cholesterol'). When they blocked TRPM4 using a drug called 9-phenanthrol (9-Phe), the treated mice developed more stable arterial plaques — even though the total amount of plaque was not reduced. Stable plaques are less likely to rupture and cause heart attacks or strokes, making this an important distinction. At the cellular level, the research found that high levels of oxidized LDL triggered a self-destruction process in endothelial cells involving a pathway called AMPK-Beclin1-mediated autophagy (a cellular 'self-eating' process that, when excessive, leads to cell death). Blocking TRPM4 interrupted this chain of events, reducing both excessive autophagy and cell death (apoptosis). The drug also helped preserve the cells' ability to move and reduced their release of inflammatory 'stickiness' molecules that attract immune cells and contribute to plaque buildup. When researchers artificially reactivated the AMPK signaling step using a separate drug (AICAR), the protective effects of 9-Phe were cancelled out, confirming that TRPM4 works through this specific pathway. This research suggests that TRPM4 could be a new therapeutic target for atherosclerosis treatment, with the goal of stabilizing dangerous plaques rather than simply reducing their size. Since plaque rupture is the main cause of heart attacks and strokes, therapies that improve plaque stability could have significant clinical value. However, these findings are currently based on mouse models and cell culture experiments, and further research would be needed to determine whether targeting TRPM4 is safe and effective in humans.
Ding X, Zhao R, Wu W, Huang D, Wang M, Wu Y, et al.. (2026). Pharmacological inhibition of TRPM4 channel stabilizes atherosclerotic plaque via inhibiting AMPK-Beclin1-mediated autophagy.. European journal of pharmacology. https://doi.org/10.1016/j.ejphar.2026.179031