Department of Respiratory Medicine & Department of Geriatric, Hunan Provincial People's Hospital/The First Affiliated Hospital of Hunan Normal University, Changsha, 410016, Hunan, People's Republic of China.
State Key Lab of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510120, Guangdong, People's Republic of China.
Respir Res. 2021 Jan 6;22(1):8. doi: 10.1186/s12931-020-01598-4.
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.
We assessed the expression pattern, mitogenetic effect, and mechanism of action of RELM-β in a rat HPH model and in hPASMCs.
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 Ca 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 Ca inhibitor.
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 Ca-dependent PI3K/Akt/mTOR and PKC/MAPK pathways.
肺动脉平滑肌细胞（PASMC）增殖在缺氧诱导的肺动脉高压（HPH）中起着至关重要的作用。先前的研究发现，抵抗素样分子β（RELM-β）在培养的人 PASMC（hPASMC）中对缺氧有新的上调反应。已经报道 RELM-β 促进 hPASMC 增殖，并参与 PAH 患者的肺血管重塑。然而，RELM-β 在 HPH 中的表达模式、作用和作用机制尚不清楚。
我们评估了 RELM-β 在大鼠 HPH 模型和 hPASMC 中的表达模式、有丝分裂效应和作用机制。
RELM-β 的过表达导致 HPH 大鼠模型中的血流动力学变化类似于慢性缺氧引起的变化，包括平均右心室收缩压（mRVSP）、右心室肥厚指数（RVHI）和小肺动脉增厚增加。RELM-β 的敲低部分阻断了缺氧引起的 mRVSP、RVHI 和血管重塑的增加。PI3K、Akt、mTOR、PKC 和 MAPK 蛋白的磷酸化水平分别通过 RELM-β 基因过表达或沉默显著上调或下调。重组 RELM-β 蛋白增加原代培养的 hPASMC 中的细胞内 Ca 浓度并促进 hPASMC 增殖。RELM-β 对 hPASMC 的促有丝分裂作用以及 PI3K、Akt、mTOR、PKC 和 MAPK 的磷酸化作用被 Ca 抑制剂抑制。
我们的研究结果表明，RELM-β 在 HPH 的发展中起细胞因子样生长因子的作用，而 RELM-β 的作用可能是通过 Ca 依赖性 PI3K/Akt/mTOR 和 PKC/MAPK 途径介导的。
