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.
Highlights
According to consensus of the Fifth World Symposium of Pulmonary Hypertension held in Nice, France, in 2013, chronic hypoxia-induced pulmonary hypertension (CHPH) belongs to group 3 of pulmonary hypertension (PH)
As is well known, during the PH development, the hypoxic elevation of [Ca2+]i due to enhanced store-operated Ca2+ entry (SOCE) has a key element in promoting the pulmonary vasoconstriction and proliferation, together acting as primary vessel pathology feature underlying the pathogenesis of PH
According to our previous studies, we have proved the hypoxic upregulation of either the store-operated calcium channels (SOCCs) core components[41] or the important SOCCregulated proteins,[42] all contributed to the hypoxic-triggered SOCE in pulmonary arterial smooth muscle cells (PASMCs)
Summary
According to consensus of the Fifth World Symposium of Pulmonary Hypertension held in Nice, France, in 2013, chronic hypoxia-induced pulmonary hypertension (CHPH) belongs to group 3 of pulmonary hypertension (PH). CHPH is characterized by excessive contraction, proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), which progressively leads to the thickening and remodeling of distal pulmonary arteries (PAs). The increase of intracellular free calcium concentration ([Ca2+]i) is a major trigger for pulmonary vasoconstriction and the proliferation and migration of PASMCs.[2] Among the multiple pathways that can lead to increase in [Ca2+]i, the hypoxia-induced enhanced store-operated Ca2+ entry (SOCE) through store-operated calcium channels (SOCCs) largely accounts for the elevated [Ca2+]i in PASMCs.[3,4] SOCCs are mainly constituted by canonical transient receptor potential channel (TRPC) and calcium release-activated calcium modulator ( called Orai).[5,6,7,8] Orai consists of three members, Orai[1], Orai[2] and Orai[3]. Orai[1] exists either as a homodimer or homotetramer; while upon activation, it forms a hexamer and mediates Ca2+ release-activated Ca2+ current (ICRAC), a highly Ca2+-selective and nonvoltage-gated current.[11,12,13,14,15] The activation kinetics of Orai[1] are relatively slow and determined by the rate of Ca2+ depletion as well as the translocation rate of both
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
