Inhibition Of Orai1 Store-Operated Calcium Channel Prevents Foam Cell Formation And Atherosclerosis

Objective To determine the role of orai1 store-operated Ca2+ entry in foam cell formation and atherogenesis.Approach and Results Acute administration of oxidized low-density lipoprotein (oxLDL) activates an orai1-dependent Ca2+ entry in macrophages. Chelation of intracellular Ca2+, inhibition of orai1 store-operated Ca2+ entry, or knockdown of orai1 dramatically inhibited oxLDL-induced upregulation of scavenger receptor A, uptake of modified LDL, and foam cell formation. Orai1-dependent Ca2+ entry induces scavenger receptor A expression and foam cell formation through activation of calcineurin but not calmodulin kinase II. Activation of nuclear factor of activated T cells is not involved in calcineurin signaling to foam cell formation. However, oxLDL dephosohorylates and activates apoptosis signal-regulating kinase 1 in macrophages. Orai1 knockdown prevents oxLDL-induced apoptosis signal-regulating kinase 1 activation. Knockdown of apoptosis signal-regulating kinase 1, or inhibition of its downstream effectors, JNK and p38 mitogen-activated protein kinase, reduces scavenger receptor A expression and foam cell formation. Notably, orai1 expression is increased in atherosclerotic plaques of apolipoprotein E-/- mice fed with high-cholesterol diet. Knockdown of orai1 with adenovirus harboring orai1 siRNA or inhibition of orai1 Ca2+ entry with SKF96365 for 4 weeks dramatically inhibits atherosclerotic plaque development in high-cholesterol diet feeding apolipoprotein E-/- mice. In addition, inhibition of orai1 Ca2+ entry prevents macrophage apoptosis in atherosclerotic plaque. Moreover, the expression of inflammatory genes in atherosclerotic lesions and the infiltration of myeloid cells into the aortic sinus plaques are decreased after blocking orai1 signaling.Conclusions Orai1-dependent Ca2+ entry promotes atherogenesis possibly by promoting foam cell formation and vascular inflammation, rendering orai1 Ca2+ channel a potential therapeutic target against atherosclerosis.