title: Hypoxia-Induced Mitogenic Factor Acts as a Nonclassical Ligand of Calcium-Sensing Receptor, Therapeutically Exploitable for Intermittent Hypoxia-Induced Pulmonary Hypertension.
abstract: Hypoxia-induced mitogenic factor (HIMF) is an inflammatory cytokine playing important role(s) in the development of hypoxic pulmonary hypertension. The molecular target mediating HIMF-stimulated downstream events remains unclear. The coimmunoprecipitation screen identified extracellular calcium-sensing receptor (CaSR) as the binding partner for HIMF in pulmonary artery smooth muscle cells. The yeast 2-hybrid assay then revealed the binding of HIMF to the intracellular, not the extracellular, domain of extracellular CaSR. The binding of HIMF enhanced the activity of extracellular CaSR and mediated hypoxia-evoked proliferation of pulmonary artery smooth cells and the development of pulmonary vascular remodeling and pulmonary hypertension, all of which was specifically attenuated by a synthesized membrane-permeable peptide flanking the core amino acids of the intracellular binding domain of extracellular CaSR. Thus, HIMF induces pulmonary hypertension as a nonclassical ligand of extracellular CaSR, and the binding motif of extracellular CaSR can be therapeutically exploitable.
authors.affiliation: From the Department of Pathophysiology, School of Basic Medicine (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Q. Hu), Key Laboratory of Pulmonary Diseases of Ministry of Health (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Y.L., J.Z., J.L., T.W., Q. Hu), Department of Pathology, Tongji Hospital (Y.L., J.L.), Department of Pathology, Union Hospital (J.Z.), Department of Respiratory and Critical Care Medicine (T.W.), and Department of Cardiothoracic and Vascular Surgery, Tongji Hospital (X.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Xianqin
authors.initials: X
authors.lastname: Zeng
authors.affiliation: From the Department of Pathophysiology, School of Basic Medicine (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Q. Hu), Key Laboratory of Pulmonary Diseases of Ministry of Health (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Y.L., J.Z., J.L., T.W., Q. Hu), Department of Pathology, Tongji Hospital (Y.L., J.L.), Department of Pathology, Union Hospital (J.Z.), Department of Respiratory and Critical Care Medicine (T.W.), and Department of Cardiothoracic and Vascular Surgery, Tongji Hospital (X.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Liping
authors.initials: L
authors.lastname: Zhu
authors.affiliation: From the Department of Pathophysiology, School of Basic Medicine (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Q. Hu), Key Laboratory of Pulmonary Diseases of Ministry of Health (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Y.L., J.Z., J.L., T.W., Q. Hu), Department of Pathology, Tongji Hospital (Y.L., J.L.), Department of Pathology, Union Hospital (J.Z.), Department of Respiratory and Critical Care Medicine (T.W.), and Department of Cardiothoracic and Vascular Surgery, Tongji Hospital (X.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Rui
authors.initials: R
authors.lastname: Xiao
authors.affiliation: From the Department of Pathophysiology, School of Basic Medicine (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Q. Hu), Key Laboratory of Pulmonary Diseases of Ministry of Health (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Y.L., J.Z., J.L., T.W., Q. Hu), Department of Pathology, Tongji Hospital (Y.L., J.L.), Department of Pathology, Union Hospital (J.Z.), Department of Respiratory and Critical Care Medicine (T.W.), and Department of Cardiothoracic and Vascular Surgery, Tongji Hospital (X.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Bingxun
authors.initials: B
authors.lastname: Liu
authors.affiliation: From the Department of Pathophysiology, School of Basic Medicine (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Q. Hu), Key Laboratory of Pulmonary Diseases of Ministry of Health (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Y.L., J.Z., J.L., T.W., Q. Hu), Department of Pathology, Tongji Hospital (Y.L., J.L.), Department of Pathology, Union Hospital (J.Z.), Department of Respiratory and Critical Care Medicine (T.W.), and Department of Cardiothoracic and Vascular Surgery, Tongji Hospital (X.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Mengxiang
authors.initials: M
authors.lastname: Sun
authors.affiliation: From the Department of Pathophysiology, School of Basic Medicine (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Q. Hu), Key Laboratory of Pulmonary Diseases of Ministry of Health (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Y.L., J.Z., J.L., T.W., Q. Hu), Department of Pathology, Tongji Hospital (Y.L., J.L.), Department of Pathology, Union Hospital (J.Z.), Department of Respiratory and Critical Care Medicine (T.W.), and Department of Cardiothoracic and Vascular Surgery, Tongji Hospital (X.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Fangbo
authors.initials: F
authors.lastname: Liu
authors.affiliation: From the Department of Pathophysiology, School of Basic Medicine (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Q. Hu), Key Laboratory of Pulmonary Diseases of Ministry of Health (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Y.L., J.Z., J.L., T.W., Q. Hu), Department of Pathology, Tongji Hospital (Y.L., J.L.), Department of Pathology, Union Hospital (J.Z.), Department of Respiratory and Critical Care Medicine (T.W.), and Department of Cardiothoracic and Vascular Surgery, Tongji Hospital (X.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Hao
authors.affiliation: From the Department of Pathophysiology, School of Basic Medicine (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Q. Hu), Key Laboratory of Pulmonary Diseases of Ministry of Health (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Y.L., J.Z., J.L., T.W., Q. Hu), Department of Pathology, Tongji Hospital (Y.L., J.L.), Department of Pathology, Union Hospital (J.Z.), Department of Respiratory and Critical Care Medicine (T.W.), and Department of Cardiothoracic and Vascular Surgery, Tongji Hospital (X.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Yankai
authors.initials: Y
authors.lastname: Lu
authors.affiliation: From the Department of Pathophysiology, School of Basic Medicine (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Q. Hu), Key Laboratory of Pulmonary Diseases of Ministry of Health (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Y.L., J.Z., J.L., T.W., Q. Hu), Department of Pathology, Tongji Hospital (Y.L., J.L.), Department of Pathology, Union Hospital (J.Z.), Department of Respiratory and Critical Care Medicine (T.W.), and Department of Cardiothoracic and Vascular Surgery, Tongji Hospital (X.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Jiwei
authors.initials: J
authors.lastname: Zhang
authors.affiliation: From the Department of Pathophysiology, School of Basic Medicine (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Q. Hu), Key Laboratory of Pulmonary Diseases of Ministry of Health (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Y.L., J.Z., J.L., T.W., Q. Hu), Department of Pathology, Tongji Hospital (Y.L., J.L.), Department of Pathology, Union Hospital (J.Z.), Department of Respiratory and Critical Care Medicine (T.W.), and Department of Cardiothoracic and Vascular Surgery, Tongji Hospital (X.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Jiansha
authors.initials: J
authors.lastname: Li
authors.affiliation: From the Department of Pathophysiology, School of Basic Medicine (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Q. Hu), Key Laboratory of Pulmonary Diseases of Ministry of Health (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Y.L., J.Z., J.L., T.W., Q. Hu), Department of Pathology, Tongji Hospital (Y.L., J.L.), Department of Pathology, Union Hospital (J.Z.), Department of Respiratory and Critical Care Medicine (T.W.), and Department of Cardiothoracic and Vascular Surgery, Tongji Hospital (X.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.affiliation: From the Department of Pathophysiology, School of Basic Medicine (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Q. Hu), Key Laboratory of Pulmonary Diseases of Ministry of Health (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Y.L., J.Z., J.L., T.W., Q. Hu), Department of Pathology, Tongji Hospital (Y.L., J.L.), Department of Pathology, Union Hospital (J.Z.), Department of Respiratory and Critical Care Medicine (T.W.), and Department of Cardiothoracic and Vascular Surgery, Tongji Hospital (X.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wei
authors.affiliation: From the Department of Pathophysiology, School of Basic Medicine (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Q. Hu), Key Laboratory of Pulmonary Diseases of Ministry of Health (X.Z., L.Z., R.X., B.L., M.S., F.L., Q. Hao, Y.L., J.Z., J.L., T.W., Q. Hu), Department of Pathology, Tongji Hospital (Y.L., J.L.), Department of Pathology, Union Hospital (J.Z.), Department of Respiratory and Critical Care Medicine (T.W.), and Department of Cardiothoracic and Vascular Surgery, Tongji Hospital (X.W.), Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China. qinghuaa@mails.tjmu.edu.cn 16654396@qq.com.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Hu
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D004195:Disease Models, Animal; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000378:metabolism*; D000860:Hypoxia / Q000150:complications / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011485:Protein Binding; D011651:Pulmonary Artery / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044169:Receptors, Calcium-Sensing / Q000378:metabolism*
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D044169:Receptors, Calcium-Sensing
keywords: chronic hypoxia; extracellular calcium-sensing receptor; hypoxia-induced mitogenic factor; hypoxic pulmonary hypertension; intracellular domain