Hypoxia-Induced Mitogenic Factor Acts as a Nonclassical Ligand of Calcium-Sensing Receptor, Therapeutically Exploitable for Intermittent Hypoxia-Induced Pulmonary Hypertension

Abstract

Hypoxia-induced mitogenic factor (HIMF) is an inflammatory cytokine playing important role(s) in the development of hypoxic pulmonary hypertension. The molecular target mediating HIMF-stimulated downstream events remains unclear. The coimmunoprecipitation screen identified extracellular calcium-sensing receptor (CaSR) as the binding partner for HIMF in pulmonary artery smooth muscle cells. The yeast 2-hybrid assay then revealed the binding of HIMF to the intracellular, not the extracellular, domain of extracellular CaSR. The binding of HIMF enhanced the activity of extracellular CaSR and mediated hypoxia-evoked proliferation of pulmonary artery smooth cells and the development of pulmonary vascular remodeling and pulmonary hypertension, all of which was specifically attenuated by a synthesized membrane-permeable peptide flanking the core amino acids of the intracellular binding domain of extracellular CaSR. Thus, HIMF induces pulmonary hypertension as a nonclassical ligand of extracellular CaSR, and the binding motif of extracellular CaSR can be therapeutically exploitable.

Resistin-like Molecule β Acts as a Mitogenic Factor in Hypoxic Pulmonary Hypertension via Ca2+ dependent PI3K/Akt/mTOR and PKC/MAPKs Signaling Pathway

“…Previous study has demonstrated that RELM-α induced intracellular calcium release via PLC-IP3 pathway [16] . A recent study found RELM-α has a calcium binding site called CaSR(Ca 2+ -sensing receptor) and induced Ca 2+ influx in a SOCE(store-operated calcium entry) dependent manner [21,36,37] . Intracellular free calcium ([Ca 2+ ]i) is a well known intracellular second messenger involved in the development of cell proliferation [38] .…”

“…through extracellular calcium influx in PASMCs [16,21] . To observe the direct effect of RELM-β on cell proliferation and Ca 2+ signaling, we prepared primary cultured PASMCs.…”

“…Both PI3K/Akt and PKC signaling pathways activate Cyclin E/D1 and cyclin-dependent kinase(CDK) 2/4, which promote cell proliferation and differentiation [20] . A recent study identified HIMF increases intracellular Ca 2+ concentration through CaSR(Ca 2+ -sensing receptor) and a SOCE(store-operated calcium entry) dependent manner, induces PASMC proliferation, leading to pulmonary hypertension [21] . Since RELM-β is known as a functional substitute for HIMF in humans [12] , we next sought to determine whether RELM-β has the capacity to stimulate Ca 2+ release in PASMC.…”

Expression and distribution of HIF-1α, HIF-2α, VEGF, VEGFR-2 and HIMF in the kidneys of Tibetan sheep, plain sheep and goat

“…It was reported as a lung specific growth factor, involving in lung cell proliferation and regulation of compensatory lung growth [27]. HIMF has functions of angiogenic and vasoconstrictive [28]. In lung epithelial cells of mouse, HIMF enhances VEGF production in a PI-3K/Akt-NF-κB signaling pathway-dependent manner [13].…”

Pathogenic role of ion channels in pulmonary arterial hypertension

“…Zeng et al . () first demonstrated that mitochondrial H 2 O 2 ‐sensitized CaSRs, activated by extracellular Ca 2+ , mediate an increase of hypoxia‐induced Ca 2+ entry and initiates hypoxic pulmonary vasoconstriction. Monocrotaline enhanced the assembly of CaSRs, triggered the mobilization of calcium signalling, damaged pulmonary artery endothelial cells and induced pulmonary hypertension (in rat studies).…”