Inhibiting Endothelial SMS2 Alleviates Atherosclerosis by Blocking Endothelial‑Mesenchymal Transition Through Boosted Fatty Acid Oxidation

BACKGROUND: Endothelial-to-mesenchymal transition (EndMT) is implicated in atherosclerosis by contributing to endothelial dysfunction (ED). SMS2 (sphingomyelin synthase 2), a key enzyme in sphingomyelin synthesis, plays a significant role in both ED and atherosclerosis. Nonetheless, the precise mechanisms of SMS2-associated ED, and its potential modulation via EndMT remain unexplored in the context of ED and atherosclerosis progression. METHODS: mice, and human atherosclerotic plaques. RESULTS: mice enhances atherosclerosis, and SMS2 positively correlates with Wnt/β-catenin, EndMT, and ED, but inversely correlates with PPARγ activity and fatty acid oxidation. Furthermore, in the unstable atherosclerosis plaques of humans, the expression of SMS2 in endothelial cells is significantly higher compared with that in stable plaques. The relationship between SMS2 and Wnt/β-catenin, EndMT, ED, PPARγ, and fatty acid oxidation aligns with the aforementioned findings. CONCLUSIONS: SMS2 can activate the Wnt/β-catenin pathway, which is inversely correlated with the activity of PPARγ and fatty acid oxidation. This process facilitates EndMT and ED, ultimately contributing to the initiation and development of atherosclerosis. These findings suggest that inhibition of endothelial SMS2 activity with Ly93 could be beneficial for the treatment of atherosclerosis.