Author:
Fan Chunling,Su Qingning,Li Yun,Liang Lihua,Angelini Daniel J.,Guggino William B.,Johns Roger A.
Abstract
Hypoxia-induced mitogenic factor (HIMF), also known as “found in inflammatory zone 1” (FIZZ1) or resistin-like molecule-α (RELMα), is a profound vasoconstrictor of the pulmonary circulation and a strong mitogenic factor in pulmonary vascular smooth muscle. To further understand the mechanism of these contractile and mitogenic responses, we examined the effect of HIMF on intracellular Ca2+ in human pulmonary artery smooth muscle cells (SMC). Ca2+ imaging in fluo 4-loaded human pulmonary artery SMC revealed that recombinant murine HIMF increased intracellular Ca2+ concentration ([Ca2+]i) in a sustained and oscillatory manner. This increase occurred independent of extracellular Ca2+ influx. Pretreatment of human pulmonary artery SMC with U-73122, a specific inhibitor of phosphatidylinositol-phospholipase C (PLC) completely prevented the HIMF-induced Ca2+ signal. The [Ca2+]i increase was also abolished by pretreatment with 2-aminoethoxydiphenyl borate (2-APB), an inositol 1,4,5-trisphosphate (IP3) receptor antagonist. Ryanodine pretreatment did not affect initiation of [Ca2+]i activation or internal release but reduced [Ca2+]i at the plateau phase. Pretreatment with the Gαi-specific inhibitor pertussis toxin and the Gαs-specific inhibitor NF-449 did not block the Ca2+ signal. Knockdown of Gαq/11 expression did not prevent Ca2+ release, but the pattern of Ca2+ release changed from the sustained oscillatory transients with prolonged plateau to a series of short [Ca2+]i transients that return to baseline. However, pretreatment with the tyrosine kinase inhibitor genistein completely inhibited the internal Ca2+ release. These results demonstrate that HIMF can stimulate intracellular Ca2+ release in human pulmonary artery SMC through the PLC signaling pathway in an IP3- and tyrosine phosphorylation-dependent manner and that Gαq/11 protein-coupled receptor and ryanodine receptor contribute to the increase of [Ca2+]i.
Publisher
American Physiological Society
Subject
Cell Biology,Physiology (medical),Pulmonary and Respiratory Medicine,Physiology
Cited by
29 articles.
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