Inhibition of Orai1 Store–Operated Calcium Channel Prevents Foam Cell Formation and Atherosclerosis

摘要: Objective— To determine the role of orai1 store–operated Ca 2+ entry in foam cell formation and atherogenesis. Approach Results— Acute administration oxidized low-density lipoprotein (oxLDL) activates an orai1-dependent macrophages. Chelation intracellular , inhibition entry, or knockdown dramatically inhibited oxLDL-induced upregulation scavenger receptor A, uptake modified LDL, formation. Orai1-dependent induces A expression through activation calcineurin but not calmodulin kinase II. Activation nuclear factor activated T cells is involved signaling to However, oxLDL dephosohorylates apoptosis signal–regulating 1 Orai1 prevents activation. Knockdown 1, its downstream effectors, JNK p38 mitogen-activated protein kinase, reduces Notably, increased atherosclerotic plaques apolipoprotein E −/− mice fed with high-cholesterol diet. adenovirus harboring siRNA SKF96365 for 4 weeks inhibits plaque development diet feeding mice. In addition, macrophage plaque. Moreover, inflammatory genes lesions infiltration myeloid into aortic sinus are decreased after blocking signaling. Conclusions— promotes atherogenesis possibly by promoting vascular inflammation, rendering channel a potential therapeutic target against atherosclerosis.