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This Article Full Text Full Text (PDF) All Versions of this Article: 297/2/L263    most recent 90416.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Google Scholar Articles by Fan, C. Articles by Johns, R. A. PubMed PubMed Citation Articles by Fan, C. Articles by Johns, R. A.

Hypoxia-induced mitogenic factor/FIZZ1 induces intracellular calcium release through the PLC-IP₃ pathway

Departments of ¹Anesthesiology and Critical Care Medicine and ²Physiology, School of Medicine, Johns Hopkins University, Baltimore, Maryland

Submitted 5 August 2008 ; accepted in final form 4 May 2009

Hypoxia-induced mitogenic factor (HIMF), also known as "found in inflammatory zone 1" (FIZZ1) or resistin-like molecule- (RELM), 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 G_i-specific inhibitor pertussis toxin and the G_s-specific inhibitor NF-449 did not block the Ca²⁺ signal. Knockdown of G_q/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 G_q/11 protein-coupled receptor and ryanodine receptor contribute to the increase of [Ca²⁺]_i.

resistin-like molecule-; inositol 1,4,5-trisphosphate receptor; phospholipase C; tyrosine phosphorylation; pulmonary vascular smooth muscle

This article has been cited by other articles:

				R. A. Johns and K. Yamaji-Kegan Unveiling cell phenotypes in lung vascular remodeling Am J Physiol Lung Cell Mol Physiol, December 1, 2009; 297(6): L1056 - L1058. [Full Text] [PDF]