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

Abstract

Objective-To determine the role of orai1 store-operated Ca 2+ entry in foam cell formation and atherogenesis. Approach and Results-Acute administration of oxidized low-density lipoprotein (oxLDL) activates an orai1-dependent Ca 2+ entry in macrophages. Chelation of intracellular Ca 2+, inhibition of orai1 store-operated Ca 2+ entry, or knockdown of orai1 dramatically inhibited oxLDL-induced upregulation of scavenger receptor A, uptake of modified LDL, and foam cell formation. Orai1-dependent Ca 2+ 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 mitogenactivated 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 Ca 2+ entry with SKF96365 for 4 weeks dramatically inhibits atherosclerotic plaque development in high-cholesterol diet feeding apolipoprotein E −/− mice. In addition, inhibition of orai1 Ca 2+ 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

Luteolin Attenuates Foam Cell Formation and Apoptosis in Ox-LDL-Stimulated Macrophages by Enhancing Autophagy

“…Furthermore, in RAW264.7 macrophage-derived foam cells, the activation of autophagy ameliorates cholesterol accumulation through an ABCA1-dependent pathway that mediates cholesterol efflux. Meanwhile, it is well documented that the accumulation of intracellular cholesterol is also crucial to induce macrophage apoptosis in vivo and in vitro [34,35]. Similar to our previous study [14], we found that autophagy activation is protective against luteolin-induced apoptosis in ox-LDL-induced macrophages.…”

Store-operated calcium entry-activated autophagy protects EPC proliferation via the CAMKK2-MTOR pathway in ox-LDL exposure

“…Previous studies have focused on ox-LDL-induced apoptosis in VSMCs, [38][39][40] endothelial cells [41][42][43][44] and EPCs. 45 The differences in oxidative status, concentration and the treatment time of ox-LDL as well as cell species might account for the different effects of our ] i measurement.…”

Reactive Oxygen Species Generation and Atherosclerosis

“…[4][5][6] This, in addition to the accumulation of cholesterol and smooth muscle cells (SMCs) in the intima, leads to the transformation of monocytes into foam cells, which consume dead cells and lipids. [7][8][9] The atherogenic process involves multiple cell types, that is, endothelial cells (ECs), 10 SMCs, 11 immune cells, 12 and stem/progenitor cells, 13 in which levels of both intracellular and extracellular reactive oxygen and nitrogen species play a fundamental role in vascular cell homoeostasis and eventually affects the development of atherosclerosis.…”