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2021-01-19T08:53:45Z urn:hdl:10324/45068 Nonsteroidal anti-inflammatory drugs inhibit vascular smooth muscle cell proliferation by enabling the Ca2+-dependent inactivation of calcium release-activated calcium/Orai channels normally prevented by mitocondria Muñoz Conejero, Eva Valero, Ruth Ana Quintana, Ariel Hoth, Markus Núñez Llorente, Lucía Villalobos Jorge, Carlos Producción Científica Abnormal vascular smooth muscle cell (VSMC) proliferation contributes to occlusive and proliferative disorders of the vessel wall. Salicylate and other nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit VSMC proliferation by an unknown mechanism unrelated to anti-inflammatory activity. In search for this mechanism, we have studied the effects of salicylate and other NSAIDs on subcellular Ca2+ homeostasis and Ca2+-dependent cell proliferation in rat aortic A10 cells, a model of neointimal VSMCs. We found that A10 cells displayed both store-operated Ca2+ entry (SOCE) and voltage-operated Ca2+ entry (VOCE), the former being more important quantitatively than the latter. Inhibition of SOCE by specific Ca2+ released-activated Ca2+ (CRAC/Orai) channels antagonists prevented A10 cell proliferation. Salicylate and other NSAIDs, including ibuprofen, indomethacin, and sulindac, inhibited SOCE and thereby Ca2+-dependent, A10 cell proliferation. SOCE, but not VOCE, induced mitochondrial Ca2+ uptake in A10 cells, and mitochondrial depolarization prevented SOCE, thus suggesting that mitochondrial Ca2+ uptake controls SOCE (but not VOCE) in A10 cells. NSAIDs depolarized mitochondria and prevented mitochondrial Ca2+ uptake, suggesting that they favor the Ca2+-dependent inactivation of CRAC/Orai channels. NSAIDs also inhibited SOCE in rat basophilic leukemia cells where mitochondrial control of CRAC/Orai is well established. NSAIDs accelerate slow inactivation of CRAC currents in rat basophilic leukemia cells under weak Ca2+ buffering conditions but not in strong Ca2+ buffer, thus excluding that NSAIDs inhibit SOCE directly. Taken together, our results indicate that NSAIDs inhibit VSMC proliferation by facilitating the Ca2+-dependent inactivation of CRAC/Orai channels which normally is prevented by mitochondria clearing of entering Ca2+. 2021-01-19T08:53:45Z 2021-01-19T08:53:45Z 2011 info:eu-repo/semantics/article Journal of Biological Chemistry, 2011, vol. 286, n. 18. p. 16186-16196 0021-9258 http://uvadoc.uva.es/handle/10324/45068 10.1074/jbc.M110.198952 eng https://www.sciencedirect.com/science/article/pii/S0021925820514361?via%3Dihub info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by-nc-nd/3.0/ © 2011 Elsevier Attribution-NonCommercial-NoDerivs 3.0 Unported Elsevier