RELM-β knockout inhibits the development of hypoxia-induced pulmonary hypertension through PLC-IP3R-Ca2+ signaling pathway
Author:
Liu Guoyu1, Tian Heshen2, Liu Yi3, Xing Yan3, Wu Ying4, Liu Lei4, Fu Daiyan4, Chen Huilian3, Zhang Chao3, Dai Aiguo3
Affiliation:
1. The Second Affiliated Hospital of The Army Medical University 2. Second Affiliated Hospital of Zhejiang University School of Medicine 3. Hunan University of Chinese Medicine 4. Hunan Provincial People’s Hospital, The First Affiliated Hospital of Hunan Normal University
Abstract
Abstract
Purpose Pulmonary vascular remodeling (PVR) is an important pathological mechanism of hypoxia-induced pulmonary hypertension (HPH), in which the proliferation of pulmonary artery smooth muscle cells (PASMCs) plays an important role. Resistin-like molecule beta (RELM-β), a secretory protein, can promote the proliferation of PASMCs induced by hypoxia. As an important signaling molecule, Ca2+ plays an important role in cell proliferation. RELM-β can regulate cell proliferation by changing the intracellular calcium concentration ([Ca2+]i), but the specific regulatory mechanism of RELM-β on Ca2+ and the pathogenesis of HPH has not been fully elucidated.
Methods We employed both in vivo and in vitro RELM-β knockout (RELM-β-/-) models to examine the effects of RELM-β on pulmonary hemodynamics, PASMCs proliferation, intracellular Ca2+ release, and associated mechanisms.
Results The expression of RELM-β increased in rat HPH model and hypoxia treated PASMCs, which led to pulmonary hemodynamic changes (increased mean pulmonary artery pressure (mPAP), right ventricular hypertrophy, pulmonary artery thickening) and PASMCs proliferation. However, knockout of RELM-β had the opposite effect. RELM-β deletion decreased the expression of phospholipase C (PLC), inositol 1,4,5-trisphosphate (IP3) receptor (IP3R), and [Ca2+]i. In addition, inhibition of PLC and IP3R can reduce [Ca2+]i.
Conclusion Our research results have confirmed the role of RELM-β as a cytokine-like growth factor in the proliferation of PASMCs and contribute to HPH. This was achieved by upregulating [Ca2+]i through the PLC/IP3R pathway.
Publisher
Research Square Platform LLC
Reference42 articles.
1. 1. Chai T, Qiu C, Xian Z, Lu Y, Zeng Y, Li J (2022) A narrative review of research advances in hypoxic pulmonary hypertension. Ann Transl Med 10:230. http://doi:10.21037/atm-22-259 2. 2. Wang C, Xu J, Yang L, Xu Y, Zhang X, Bai C, Kang J, Ran P, Shen H, Wen F, Huang K, Yao W, Sun T, Shan G, Yang T, Lin Y, Wu S, Zhu J, Wang R, Shi Z, Zhao J, Ye X, Song Y, Wang Q, Zhou Y, Ding L, Yang T, Chen Y, Guo Y, Xiao F, Lu Y, Peng X, Zhang B, Xiao D, Chen CS, Wang Z, Zhang H, Bu X, Zhang X, An L, Zhang S, Cao Z, Zhan Q, Yang Y, Cao B, Dai H, Liang L, He J (2018) Prevalence and risk factors of chronic obstructive pulmonary disease in china (the china pulmonary health [cph] study): A national cross-sectional study. Lancet 391:1706–1717. http://doi:10.1016/s0140-6736(18)30841-9 3. 3. Skjørten I, Hilde JM, Melsom MN, Hansteen V, Steine K, Humerfelt S (2013) Pulmonary artery pressure and pao2 in chronic obstructive pulmonary disease. Respir Med 107:1271–1279. http://doi:10.1016/j.rmed.2013.03.021 4. 4. Minai OA, Chaouat A, Adnot S (2010) Pulmonary hypertension in copd: Epidemiology, significance, and management: Pulmonary vascular disease: The global perspective. Chest 137:39s-51s. http://doi:10.1378/chest.10-0087 5. 5. Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, Simonneau G, Peacock A, Vonk Noordegraaf A, Beghetti M, Ghofrani A, Gomez Sanchez MA, Hansmann G, Klepetko W, Lancellotti P, Matucci M, McDonagh T, Pierard LA, Trindade PT, Zompatori M, Hoeper M (2016) 2015 esc/ers guidelines for the diagnosis and treatment of pulmonary hypertension: The joint task force for the diagnosis and treatment of pulmonary hypertension of the european society of cardiology (esc) and the european respiratory society (ers): Endorsed by: Association for european paediatric and congenital cardiology (aepc), international society for heart and lung transplantation (ishlt). Eur Heart J 37:67–119. http://doi:10.1093/eurheartj/ehv317
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