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

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 beta (RELM-beta) is upregulated de novo in response to hypoxia in cultured human PASMCs (hPASMCs). RELM-beta 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-beta in HPH remain unclear. Methods: We assessed the expression pattern, mitogenetic effect, and mechanism of action of RELM-beta in a rat HPH model and in hPASMCs. Results: Overexpression of RELM-beta 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-beta 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-beta gene overexpression or silencing, respectively. Recombinant RELM-beta protein increased the intracellular Ca2+ concentration in primary cultured hPASMCs and promoted hPASMC proliferation. The mitogenic effects of RELM-beta on hPASMCs and the phosphorylation of PI3K, Akt, mTOR, PKC, and MAPK were suppressed by a Ca2+ inhibitor. Conclusions: Our findings suggest that RELM-beta acts as a cytokine-like growth factor in the development of HPH and that the effects of RELM-beta are likely to be mediated by the Ca2+-dependent PI3K/Akt/mTOR and PKC/MAPK pathways.

Automated summary

RELMB acts as a cytokine-like growth factor in the development of hypoxia-induced pulmonary hypertension, likely mediated by the Ca2+-dependent PI3K/Akt/mTOR and PKC/MAPK pathways.