Inhibition of Orai1 Store–Operated Calcium Channel Prevents Foam Cell Formation and Atherosclerosis
| Autor: | Bei-Xin Yu, Xiao-Yi Mai, Xiaofei Lv, Jie Liu, Jie-Sheng Qian, Fei-Ran Zhang, Ying-ying Liu, Jing-Song Ou, De-Yi Zeng, Qian-Qian Wu, Si-Jia Liang, Jin-Yan Shang, Jia-Guo Zhou, Jia-Ni Yuan, Ping Zhou |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Time Factors ORAI1 Protein p38 mitogen-activated protein kinases Aortic Diseases Apoptosis 030204 cardiovascular system & hematology Biology MAP Kinase Kinase Kinase 5 Transfection p38 Mitogen-Activated Protein Kinases 03 medical and health sciences Apolipoproteins E 0302 clinical medicine Cell Line Tumor Ca2+/calmodulin-dependent protein kinase Animals Humans Calcium Signaling Scavenger receptor Protein kinase A Aorta Calcium Chelating Agents Foam cell Mice Knockout Dose-Response Relationship Drug Voltage-dependent calcium channel Anticholesteremic Agents Calcineurin JNK Mitogen-Activated Protein Kinases Scavenger Receptors Class A Atherosclerosis Calcium Channel Blockers Plaque Atherosclerotic Cell biology Lipoproteins LDL Disease Models Animal Cholesterol 030104 developmental biology Biochemistry Macrophages Peritoneal Calcium RNA Interference Calcium Channels Inflammation Mediators Cardiology and Cardiovascular Medicine Foam Cells |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 36:618-628 |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | 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 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. |
| Databáze: | OpenAIRE |
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