Heshen Tian1,2, Lei Liu1, Ying Wu1, Ruiwen Wang1, Yongliang Jiang1, Ruicheng Hu1, Liming Zhu1, Linwei Li1, Yanyan Fang1, Chulan Yang1, Lianzhi Ji1, Guoyu Liu1, Aiguo Dai3,4. 1. 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. 2. State Key Lab of Respiratory Diseases, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510120, Guangdong, People's Republic of China. 3. 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. daiaiguo2003@163.com. 4. Department of Respiratory Diseases, Medical School, Hunan University of Chinese Medicine, Changsha, 410208, Hunan, People's Republic of China. daiaiguo2003@163.com.
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.
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 humanPASMCs (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 ratHPH 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.
Authors: C M Steppan; E J Brown; C M Wright; S Bhat; R R Banerjee; C Y Dai; G H Enders; D G Silberg; X Wen; G D Wu; M A Lazar Journal: Proc Natl Acad Sci U S A Date: 2001-01-16 Impact factor: 11.205
Authors: A Campo; S C Mathai; J Le Pavec; A L Zaiman; L K Hummers; D Boyce; T Housten; N Lechtzin; H Chami; R E Girgis; P M Hassoun Journal: Eur Respir J Date: 2011-02-10 Impact factor: 16.671
Authors: Rong-Ze Yang; Qing Huang; Aihua Xu; John C McLenithan; Jonathan A Eisen; Alan R Shuldiner; Serhan Alkan; Da-Wei Gong; Jonathan A Eison Journal: Biochem Biophys Res Commun Date: 2003-10-24 Impact factor: 3.575