Orai1, 2, 3 and STIM1 promote store-operated calcium entry in pulmonary arterial smooth muscle cells

Abstract

Previous studies have demonstrated that besides the classic canonical transient receptor potential channel family, Orai family and stromal interaction molecule 1 (STIM1) might also be involved in the regulation of store-operated calcium channels (SOCCs). An increase in cytosolic free Ca2+ concentration promoted by store-operated Ca2+ entry (SOCE) in pulmonary arterial smooth muscle cells (PASMCs) is a major trigger for pulmonary vasoconstriction and proliferation and migration of PASMCs. In this study, our data revealed the following: (1) in both rat distal pulmonary arteries and PASMCs, chronic hypoxia exposure upregulated the expression of Orai1 and Orai2, without affecting Orai3 and STIM1; (2) either heterozygous knockout of HIF-1α in mice or knockdown of HIF-1α in PASMCs abolished the hypoxic upregulation of Orai2, but not Orai1, suggesting the hypoxic upregulation of Orai2 depends on HIF-1α; and (3) using small interference RNA knockdown strategies, Orai1, 2, 3 and STIM1 were all shown to mediate SOCE in hypoxic PASMCs. Together, these results suggested that the components of SOCCs, including Orai1, 2, 3 and STIM1, may lead to novel therapeutic targets for the treatment of chronic hypoxia-induced pulmonary hypertension.

Bone Marrow-Derived Endothelial Progenitor Cells Contribute to Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats via Inhibition of Store-Operated Ca2+ Channels

“…Increasing evidence has suggested the important roles of Orai and TRPC channels in PAH. Orai1, Orai12, and Orai3 can promote SOCE in PASMCs and may serve as potential therapeutic targets for chronic hypoxia-induced pulmonary hypertension [ 36 ]. Dragoni et al suggested that Orai3 is overexpressed in primary myelofibrosis-endothelial colony forming cells (ECFCs) that are EPC subset and thus resulted in the upregulation of SOCE [ 37 ].…”

TRPC Channels in the SOCE Scenario

“…The function of the STIM2.3 variant still remains unclear [46,47]. Orai2 and Orai3 proteins have also been shown to drive I CRAC currents after depletion of the intracellular stores [48][49][50] and their regulation and physiological role are less known as compared to Orai1. Therefore, it is currently widely established that the Orai-STIM complex, mainly Orai1-STIM1, constitutes the highly selective CRAC channel.…”

Protease‐activated receptor 2 activates CRAC‐mediated Ca 2+ influx to cause prostate smooth muscle contraction

“…Most recent studies have shown that aberrant activation of STIM1‐Orai1 impairs the control of cellular Ca 2+ levels that cause vascular dysfunction associated with arterial hypertension . In a model of chronic hypoxia induced pulmonary hypertension, the expression of Orai1 and Orai2 were seen to be upregulated in pulmonary arteries and pulmonary arterial smooth muscle cells after chronic hypoxia exposure . Increased expression of STIM1 and Orai1 proteins have also been implicated in vascular smooth muscle cell remodeling following balloon injury in the rat carotid artery .…”

“…25 In a model of chronic hypoxia induced pulmonary hypertension, the expression of Orai1 and Orai2 were seen to be upregulated in pulmonary arteries and pulmonary arterial smooth muscle cells after chronic hypoxia exposure. 26 Increased expression of STIM1 and Orai1 proteins have also been implicated in vascular smooth muscle cell remodeling following balloon injury in the rat carotid artery. 27 Furthermore, this study also shows that upregulation of STIM1 and Orai1 is required for nuclear translocation and activation of the transcription factor nuclear factor for activated T cell (NFAT) to allow proliferation of the vascular smooth muscle cells.…”