title: 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.
  
  
  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 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.).
authors.forename: Si-Jia
authors.initials: SJ
authors.lastname: Liang
authors.affiliation: 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.).
authors.forename: De-Yi
authors.initials: DY
authors.lastname: Zeng
authors.affiliation: 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.).
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Mai
authors.affiliation: 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.).
authors.forename: Jin-Yan
authors.initials: JY
authors.lastname: Shang
authors.affiliation: 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.).
authors.forename: Qian-Qian
authors.initials: QQ
authors.lastname: Wu
authors.affiliation: 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.).
authors.forename: Jia-Ni
authors.initials: JN
authors.lastname: Yuan
authors.affiliation: 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.).
authors.forename: Bei-Xin
authors.initials: BX
authors.lastname: Yu
authors.affiliation: 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.).
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.affiliation: 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.).
authors.forename: Fei-Ran
authors.initials: FR
authors.lastname: Zhang
authors.affiliation: 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.).
authors.forename: Ying-Ying
authors.initials: YY
authors.lastname: Liu
authors.affiliation: 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.).
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Lv
authors.affiliation: 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.).
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: 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.).
authors.forename: Jing-Song
authors.initials: JS
authors.lastname: Ou
authors.affiliation: 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.). zhoujg@mail.sysu.edu.cn qjsyf@163.com.
authors.forename: Jie-Sheng
authors.initials: JS
authors.lastname: Qian
authors.affiliation: 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.). zhoujg@mail.sysu.edu.cn qjsyf@163.com.
authors.forename: Jia-Guo
authors.initials: JG
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D065096:Calcium Chelating Agents / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018345:Mice, Knockout; D000071740:ORAI1 Protein; D058226:Plaque, Atherosclerotic; D034622:RNA Interference; D051117:Scavenger Receptors, Class A / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D065096:Calcium Chelating Agents; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; C520430:Orai1 protein, mouse; D051117:Scavenger Receptors, Class A; C099252:oxidized low density lipoprotein; D002784:Cholesterol; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D019703:Calcineurin; D002118:Calcium
keywords: apoptosis; atherosclerosis; foam cells; inflammation; monocytes