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

Abstract

BACKGROUND: Pulmonary arterial smooth muscle cell (PASMC) proliferation plays a crucial role in hypoxia-induced pulmonary hypertension (HPH). Previous studies have found that resistin-like molecule β (RELM-β) is upregulated de novo in response to hypoxia in cultured human PASMCs (hPASMCs). RELM-β has been reported to promote hPASMC proliferation and is involved in pulmonary vascular remodeling in patients with PAH. However, the expression pattern, effects, and mechanisms of action of RELM-β in HPH remain unclear.METHODS: We assessed the expression pattern, mitogenetic effect, and mechanism of action of RELM-β in a rat HPH model and in hPASMCs.RESULTS: Overexpression of RELM-β caused hemodynamic changes in a rat model of HPH similar to those induced by chronic hypoxia, including increased mean right ventricular systolic pressure (mRVSP), right ventricular hypertrophy index (RVHI) and thickening of small pulmonary arterioles. Knockdown of RELM-β partially blocked the increases in mRVSP, RVHI, and vascular remodeling induced by hypoxia. The phosphorylation levels of the PI3K, Akt, mTOR, PKC, and MAPK proteins were significantly up- or downregulated by RELM-β gene overexpression or silencing, respectively. Recombinant RELM-β protein increased the intracellular Ca2+ concentration in primary cultured hPASMCs and promoted hPASMC proliferation. The mitogenic effects of RELM-β on hPASMCs and the phosphorylation of PI3K, Akt, mTOR, PKC, and MAPK were suppressed by a Ca2+ inhibitor.CONCLUSIONS: Our findings suggest that RELM-β acts as a cytokine-like growth factor in the development of HPH and that the effects of RELM-β are likely to be mediated by the Ca2+-dependent PI3K/Akt/mTOR and PKC/MAPK pathways.

Protective effects of calcyclin-binding protein against pulmonary vascular remodeling in flow-associated pulmonary arterial hypertension

“…PI3K/AKT plays a vital role in the regulation of cellular functions, including cell metabolism, growth, proliferation, survival, transcription, and protein synthesis [28]. Activation of the PI3K/AKT pathway promoted proliferation and migration of PASMCs, which is a wellrecognized characteristic of PAH [29][30][31][32]. Decrease of CacyBP/SIP effectively increased the phosphorylation levels of PI3K and AKT, resulting in a change in the phenotypic switch of PASMCs.…”

Synemin promotes pulmonary artery smooth muscle cell phenotypic switch in shunt‐induced pulmonary arterial hypertension

“…The AKT signalling pathway is a classic pathway that modulates PASMC dysfunction. Several studies have reported that the activation of AKT promotes phenotypic switch, proliferation, and migration of PASMCs, thus intensifying pulmonary vascular remodelling in PAH 25–27 . In addition, it has been demonstrated that SYN enhances the proliferation of glioblastoma cells via activation of the AKT signalling pathway 17 .…”

“…Emerging evidence has demonstrated that AKT signalling participates in the modulation of the phenotypic switch, proliferation, and migration of PASMCs in PAH. [25][26][27] In addition, Pitre et al showed that SYN positively promotes glioblastoma cell proliferation by promoting AKT activation. 17…”

“…Several studies have reported that the activation of AKT promotes phenotypic switch, proliferation, and migration of PASMCs, thus intensifying pulmonary vascular remodelling in PAH. [25][26][27] In addition, it has been demonstrated that SYN enhances the proliferation of glioblastoma cells via activation of the AKT signalling pathway. 17 Here, we provided direct evidence that SYN overexpression promoted hPASMCs dysfunction, and these effects were reversed by an AKT inhibitor.…”

MonOrail to Cure? Targeting Orai1 to Reverse Pulmonary Arterial Hypertension

“…An increase in cytosolic-free Ca 2+ and a decrease in mitochondrial Ca 2+ concentrations promote pulmonary vasoconstriction and PASMC proliferation through activation of PI3K/Akt/mTOR and MAPK pathways. 5,6 One of the important regulators of Ca 2+ homeostasis is a store-operated Ca 2+ channel, which mediates store-operated Ca 2+ entry. Store-operated Ca 2+ channel consists of the Ca 2+ channels Orai1-3 and, in part, transient receptor potential canonical channels, which are activated by stromal interacting molecules (STIM) in response to G-protein coupled receptors/PLC (phospholipase C)-induced endoplasmic reticulum-sarcoplasmic reticulum (SR) Ca 2+ store depletion.…”