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 eff...