Biomaterial Database

Sox17 Deficiency Promotes Pulmonary Arterial Hypertension via HGF/c-Met Signaling. 2022

Chan Soon Park, and Soo Hyun Kim, and Hae Young Yang, and Ju-Hee Kim, and Ralph Theo Schermuly, and Ye Seul Cho, and Hyejeong Kang, and Jae-Hyeong Park, and Eunhyeong Lee, and HyeonJin Park, and Jee Myung Yang, and Tae Wook Noh, and Seung-Pyo Lee, and Sun Sik Bae, and Jinju Han, and Young Seok Ju, and Jun-Bean Park, and Injune Kim

Graduate School of Medical Science and Engineering (C.S.P., S.H.K., H.Y.Y., J.-H.K., E.L., H.P., J.M.Y., T.W.N., J.H., Y.S.J., I.K.).

In large-scale genomic studies, Sox17, an endothelial-specific transcription factor, has been suggested as a putative causal gene of pulmonary arterial hypertension (PAH); however, its role and molecular mechanisms remain to be elucidated. We investigated the functional impacts and acting mechanisms of impaired Sox17 (SRY-related HMG-box17) pathway in PAH and explored its potential as a therapeutic target. In adult mice, Sox17 deletion in pulmonary endothelial cells (ECs) induced PAH under hypoxia with high penetrance and severity, but not under normoxia. Key features of PAH, such as hypermuscularization, EC hyperplasia, and inflammation in lung arterioles, right ventricular hypertrophy, and elevated pulmonary arterial pressure, persisted even after long rest in normoxia. Mechanistically, transcriptomic profiling predicted that the combination of Sox17 deficiency and hypoxia activated c-Met signaling in lung ECs. HGF (hepatocyte grow factor), a ligand of c-Met, was upregulated in Sox17-deficient lung ECs. Pharmacologic inhibition of HGF/c-Met signaling attenuated and reversed the features of PAH in both preventive and therapeutic settings. Similar to findings in animal models, Sox17 levels in lung ECs were repressed in 26.7% of PAH patients (4 of 15), while those were robust in all 14 non-PAH controls. HGF levels in pulmonary arterioles were increased in 86.7% of patients with PAH (13 of 15), but none of the controls showed that pattern. The downregulation of Sox17 levels in pulmonary arterioles increases the susceptibility to PAH, particularly when exposed to hypoxia. Our findings suggest the reactive upregulation of HGF/c-Met signaling as a novel druggable target for PAH treatment.

UI	MeSH Term	Description	Entries
D006976	Hypertension, Pulmonary	Increased VASCULAR RESISTANCE in the PULMONARY CIRCULATION, usually secondary to HEART DISEASES or LUNG DISEASES.	Pulmonary Hypertension
D011651	Pulmonary Artery	The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs.	Arteries, Pulmonary,Artery, Pulmonary,Pulmonary Arteries
D000081029	Pulmonary Arterial Hypertension	A progressive rare pulmonary disease characterized by high blood pressure in the PULMONARY ARTERY.	Arterial Hypertension, Pulmonary,Hypertension, Pulmonary Arterial
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D000860	Hypoxia	Sub-optimal OXYGEN levels in the ambient air of living organisms.	Anoxia,Oxygen Deficiency,Anoxemia,Deficiency, Oxygen,Hypoxemia,Deficiencies, Oxygen,Oxygen Deficiencies
D015398	Signal Transduction	The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.	Cell Signaling,Receptor-Mediated Signal Transduction,Signal Pathways,Receptor Mediated Signal Transduction,Signal Transduction Pathways,Signal Transduction Systems,Pathway, Signal,Pathway, Signal Transduction,Pathways, Signal,Pathways, Signal Transduction,Receptor-Mediated Signal Transductions,Signal Pathway,Signal Transduction Pathway,Signal Transduction System,Signal Transduction, Receptor-Mediated,Signal Transductions,Signal Transductions, Receptor-Mediated,System, Signal Transduction,Systems, Signal Transduction,Transduction, Signal,Transductions, Signal
D042783	Endothelial Cells	Highly specialized EPITHELIAL CELLS that line the HEART; BLOOD VESSELS; and lymph vessels, forming the ENDOTHELIUM. They are polygonal in shape and joined together by TIGHT JUNCTIONS. The tight junctions allow for variable permeability to specific macromolecules that are transported across the endothelial layer.	Capillary Endothelial Cells,Lymphatic Endothelial Cells,Vascular Endothelial Cells,Capillary Endothelial Cell,Cell, Capillary Endothelial,Cell, Endothelial,Cell, Lymphatic Endothelial,Cell, Vascular Endothelial,Cells, Capillary Endothelial,Cells, Endothelial,Cells, Lymphatic Endothelial,Cells, Vascular Endothelial,Endothelial Cell,Endothelial Cell, Capillary,Endothelial Cell, Lymphatic,Endothelial Cell, Vascular,Endothelial Cells, Capillary,Endothelial Cells, Lymphatic,Endothelial Cells, Vascular,Lymphatic Endothelial Cell,Vascular Endothelial Cell
D051379	Mice	The common name for the genus Mus.	Mice, House,Mus,Mus musculus,Mice, Laboratory,Mouse,Mouse, House,Mouse, Laboratory,Mouse, Swiss,Mus domesticus,Mus musculus domesticus,Swiss Mice,House Mice,House Mouse,Laboratory Mice,Laboratory Mouse,Mice, Swiss,Swiss Mouse,domesticus, Mus musculus
D055760	SOXF Transcription Factors	A subclass of closely-related SOX transcription factors. Members of this subclass are expressed in VASCULAR ENDOTHELIAL CELLS and may play a role in vasculogenesis.	Group F SOX Transcription Factors,SOX-17 Transcription Factor,SOX-18 Transcription Factor,SOX-7 Transcription Factor,SOX17 Transcription Factor,SOX18 Transcription Factor,SOX7 Transcription Factor,SOX 17 Transcription Factor,SOX 18 Transcription Factor,SOX 7 Transcription Factor,Transcription Factor, SOX-17,Transcription Factor, SOX-18,Transcription Factor, SOX-7,Transcription Factor, SOX17,Transcription Factor, SOX18,Transcription Factor, SOX7,Transcription Factors, SOXF
D019859	Proto-Oncogene Proteins c-met	Cell surface protein-tyrosine kinase receptors for HEPATOCYTE GROWTH FACTOR. They consist of an extracellular alpha chain which is disulfide-linked to the transmembrane beta chain. The cytoplasmic portion contains the catalytic domain and sites critical for the regulation of kinase activity. Mutations in the c-met proto-oncogene are associated with papillary renal carcinoma and other neoplasia.	HGF Receptor,Hepatocyte Growth Factor Receptor,c-met Proteins,met Proto-Oncogene Proteins,MET Proto-Oncogene, Receptor Tyrosine Kinase,MET Receptor Tyrosine Kinase,Receptor, HGF,Receptor, Hepatocyte Growth Factor,Receptor, Scatter Factor,Scatter Factor Receptor,c-Met Receptor Tyrosine Kinase,MET Proto Oncogene, Receptor Tyrosine Kinase,Proto Oncogene Proteins c met,Proto-Oncogene Proteins, met,c Met Receptor Tyrosine Kinase,c met Proteins,met Proto Oncogene Proteins