Pharmacological inhibition of TRPM4 channel stabilizes atherosclerotic plaque via inhibiting AMPK-Beclin1-mediated autophagy.
The study indicates that TRPM4 may contribute to atherosclerosis progression, and its inhibition could stabilize plaques, but it does not reduce plaque size.
Where it sits
this study against the rest of the aicar (acadesine) corpusSummary and findings
This study investigated the role of the TRPM4 channel in atherosclerosis using ApoE-/- mice on a high-fat diet for 16 weeks. The specific TRPM4 inhibitor 9-phenanthrol (9-Phe) was administered, revealing effects on plaque stabilization but not on plaque area reduction. AICAR (acadesine) was noted to counteract the protective effects of 9-Phe in endothelial cells exposed to oxidized low-density lipoprotein (ox-LDL).
Abstract
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<sup>-/-</sup> 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<sup>-/-</sup> 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.
Background
The study addresses the role of TRPM4 channels in atherosclerosis, a condition characterized by plaque buildup in arteries. Previous research has indicated that autophagy plays a crucial role in plaque stability, but the specific mechanisms remain unclear. Understanding the pharmacological modulation of this pathway could provide insights into potential therapeutic strategies.
Methods
The study utilized a rodent model to assess the effects of TRPM4 channel inhibition on atherosclerotic plaques. Specifics regarding the sample size, dosing regimen, and duration of treatment were not reported in the abstract. Primary outcomes focused on plaque stability and autophagy markers.
Results
Not reported in abstract.
Interpretation
The findings, while potentially significant, must be interpreted with caution due to the use of rodent models, which may not directly correlate with human outcomes. The clinical relevance of the effect sizes reported is uncertain without further context or human data. The study's implications for practice are limited by these factors.
Key findings
- Not reported in abstract.
Limitations
- Rodent model only, no human data.
- Not reported in abstract.