Liang Si-Jia, Zeng De-Yi, Mai Xiao-Yi, Shang Jin-Yan, Wu Qian-Qian, Yuan Jia-Ni, Yu Bei-Xin, Zhou Ping, Zhang Fei-Ran, Liu Ying-Ying, Lv Xiao-Fei, Liu Jie, Ou Jing-Song, Qian Jie-Sheng, Zhou Jia-Guo
From the Department of Pharmacology, Cardiac and Cerebrovascular Research Center (S.-J.L., D.-Y.Z., X.-Y.M., J.-Y.S., Q.-Q.W., J.-N.Y., B.-X.Y., F.-R.Z., Y.-Y.L., X.-F.L., J.L., J.-G.Z.) and Guangdong Province Key Laboratory of Brain Function and Disease (J.-G.Z.), Zhongshan School of Medicine, Division of Cardiac Surgery, The Key Laboratory of Assisted Circulation, Ministry of Health, The First Affiliated Hospital (J.-S.O.), and Department of Radiology, Intervention Radiology Institute, The Third Affiliated Hospital (J.-S.Q.), Sun Yat-Sen University, Guangzhou, China; and Department of Physiology and Pathophysiology, Dali University, Dali, China (P.Z.).
Arterioscler Thromb Vasc Biol. 2016 Apr;36(4):618-28. doi: 10.1161/ATVBAHA.116.307344. Epub 2016 Feb 25.
To determine the role of orai1 store-operated Ca(2+) entry in foam cell formation and atherogenesis.
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 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 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.
Orai1-dependent Ca(2+) entry promotes atherogenesis possibly by promoting foam cell formation and vascular inflammation, rendering orai1 Ca(2+) channel a potential therapeutic target against atherosclerosis.
确定Orai1依赖性钙库操纵性钙内流在泡沫细胞形成和动脉粥样硬化发生中的作用。
急性给予氧化型低密度脂蛋白（oxLDL）可激活巨噬细胞中Orai1依赖性钙内流。螯合细胞内钙、抑制Orai1依赖性钙库操纵性钙内流或敲低Orai1可显著抑制oxLDL诱导的清道夫受体A上调、修饰型LDL摄取及泡沫细胞形成。Orai1依赖性钙内流通过激活钙调神经磷酸酶而非钙调蛋白激酶II诱导清道夫受体A表达及泡沫细胞形成。活化T细胞核因子的激活不参与钙调神经磷酸酶向泡沫细胞形成的信号传导。然而，oxLDL可使巨噬细胞中的凋亡信号调节激酶1去磷酸化并激活。敲低Orai1可阻止oxLDL诱导的凋亡信号调节激酶1激活。敲低凋亡信号调节激酶1或抑制其下游效应分子JNK和p38丝裂原活化蛋白激酶可降低清道夫受体A表达及泡沫细胞形成。值得注意的是，喂食高胆固醇饮食的载脂蛋白E基因敲除（apoE(-/-)）小鼠的动脉粥样硬化斑块中Orai1表达增加。用携带Orai1小干扰RNA的腺病毒敲低Orai1或用SKF96365抑制Orai1钙内流4周可显著抑制喂食高胆固醇饮食的apoE(-/-)小鼠的动脉粥样硬化斑块发展。此外，抑制Orai1钙内流可防止动脉粥样硬化斑块中的巨噬细胞凋亡。而且，阻断Orai1信号后，动脉粥样硬化病变中炎症基因的表达及髓样细胞向主动脉窦斑块的浸润减少。
Orai1依赖性钙内流可能通过促进泡沫细胞形成和血管炎症促进动脉粥样硬化发生，使Orai1钙通道成为抗动脉粥样硬化的潜在治疗靶点。
