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검색어 | pulmonary arterial hypertension

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김인준 의과학대학원 1996 1, 3, 5, 8, 5, 7, 2, 1, 1, 1, 1, 1, 3, 3, 2, 2, 3, 1, 3, 3, 1, 1, 4, 2, 1, 1, 2, 2025
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Sox17 Deficiency Promotes Pulmonary Arterial Hypertension via HGF/c-Met Signaling CIRCULATION RESEARCH, v.131, no.10, pp.792 - 806, 2022-10
SCOPUS 30

Keywords endothelial cells hypoxia pulmonary arterial hypertension sequence analysis RNA

Sox17 Deficiency Promotes Pulmonary Arterial Hypertension via HGF/c-Met Signaling
Park, Chan Soon ; Kim, Soo Hyun ; Yang, Hae Young ; Kim, Ju-Hee ; Schermuly, Ralph Theo ; Cho, Ye Seul ; Kang, Hyejeong ; Park, Jae-Hyeong ; Lee, Eunhyeong ; Park, HyeonJin ; Yang, Jee Myung ; Noh, Tae Wook ; Lee, Seung-Pyo ; Bae, Sun Sik ; Han, Jinju ; Ju, Young Seok ; Park, Jun-Bean ; Kim, Injune

초록	Background: 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. Methods: In adult mice, Sox17 deletion in pulmonary endothelial cells (ECs) induced PAH under hypoxia with high penetrance and severity, but not under normoxia. Results: 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. Conclusions: 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.
서지사항	CIRCULATION RESEARCH, v.131, no.10, pp.792 - 806, 2022-10
ISSN	0009-7330
주제분야	Cardiovascular System & Cardiology Hematology
저자 키워드	endothelial cells hypoxia pulmonary arterial hypertension sequence analysis RNA
DOI	10.1161/CIRCRESAHA.122.320845
자료유형	Article
기관	KAIST

Comparative analysis on the anti-inflammatory/immune effect of mesenchymal stem cell therapy for the treatment of pulmonary arterial hypertension Scientific Reports, v.11, no.1, 2021-01
SCOPUS 16

Comparative analysis on the anti-inflammatory/immune effect of mesenchymal stem cell therapy for the treatment of pulmonary arterial hypertension
Oh, Seyeon ; Jang, Albert Y. ; Chae, Sehyun ; Choi, Seungbum ; Moon, Jeongsik ; Kim, Minsu ; Spiekerkoetter, Edda ; Zamanian, Roham T. ; Yang, Phillip C. ; Hwang, Daehee ; Byun, Kyunghee ; Chung, Wook-Jin

초록	Despite the advancement of targeted therapy for pulmonary arterial hypertension (PAH), poor prognosis remains a reality. Mesenchymal stem cells (MSCs) are one of the most clinically feasible alternative treatment options. We compared the treatment effects of adipose tissue (AD)-, bone marrow (BD)-, and umbilical cord blood (UCB)-derived MSCs in the rat monocrotaline-induced pulmonary hypertension (PH) model. The greatest improvement in the right ventricular function was observed in the UCB-MSCs treated group. The UCB-MSCs treated group also exhibited the greatest improvement in terms of the largest decrease in the medial wall thickness, perivascular fibrosis, and vascular cell proliferation, as well as the lowest levels of recruitment of innate and adaptive immune cells and associated inflammatory cytokines. Gene expression profiling of lung tissue confirmed that the UCB-MSCs treated group had the most notably attenuated immune and inflammatory profiles. Network analysis further revealed that the UCB-MSCs group had the greatest therapeutic effect in terms of the normalization of all three classical PAH pathways. The intravenous injection of the UCB-MSCs, compared with those of other MSCs, showed superior therapeutic effects in the PH model for the (1) right ventricular function, (2) vascular remodeling, (3) immune/inflammatory profiles, and (4) classical PAH pathways. © 2021, The Author(s).
서지사항	Scientific Reports, v.11, no.1, 2021-01
ISSN	2045-2322
주제분야	Science & Technology - Other Topics
저자 키워드
DOI	10.1038/s41598-021-81244-1
자료유형	Article
기관	DGIST

Mitochondrial HSP90 Accumulation Promotes Vascular Remodeling in Pulmonary Arterial Hypertension AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, v.198, no.1, pp.90 - 103, 2018-07
SCOPUS 91

Keywords cell metabolism cancer vascular smooth muscle cells proliferation apoptosis

Mitochondrial HSP90 Accumulation Promotes Vascular Remodeling in Pulmonary Arterial Hypertension
Boucherat, Olivier ; Peterlini, Thibaut ; Bourgeois, Alice ; Nadeau, Valerie ; Breuils-Bonnet, Sandra ; Boilet-Molez, Stephanie ; Potus, Francois ; Meloche, Jolyane ; Chabot, Sophie ; Lambert, Caroline ; Tremblay, Eve ; Chae, Young Chan ; Altieri, Dario C ; Sutendra, Gopinath ; Michelakis, Evangelos D ; Paulin, Roxane ; Provencher, Steeve ; Bonnet, Sebastien

초록	Rationale: Pulmonary arterial hypertension (PAH) is a vascular remodeling disease with a poor prognosis and limited therapeutic option. Although the mechanisms contributing to vascular remodeling in PAH are still unclear, several features, including hyper-proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs), have led to the emergence of the cancer-like concept. The molecular chaperone heat shock protein 90 (HSP90) is directly associated with malignant growth and proliferation under stress conditions. In addition to be highly expressed in the cytosol, HSP90 exists in a subcellular pool compartmentalized in the mitochondria (mtHSP90) of tumor cells, but not in normal cells, where it promotes cell survival. Objectives: We hypothesized that mtHSP90 in PAH-PASMCs represents a protective mechanism against stress promoting their proliferation and resistance to apoptosis. Measurements and Main Results: We demonstrated that in response to stress HSP90 preferentially accumulates in PAH-PASMC mitochondria (dual immunostaining, immunoblot and immunogold electron microscopy) to ensure cell survival by preserving mitochondrial DNA integrity and bioenergetics functions (Seahorse). Whereas cytosolic HSP90 inhibition displays a lack of absolute specificity for PAH-PASMCs, Gamitrinib, a specific mtHSP90 inhibitor decreased mitochondrial DNA content and repair capacity and bioenergetics functions, thus repressing PAH-PASMC proliferation (Ki67 labeling) and resistance to apoptosis (Annexin V assay) without affecting control cells. In vivo, Gamitrinib improves PAH in two experimental rat models (monocrotaline and Fawn-Hooded rat). Conclusions: Our data show for the first time that accumulation of mtHSP90 is a feature of PAH-PASMCs and key regulator of mitochondrial homeostasis contributing to vascular remodeling in PAH.
서지사항	AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, v.198, no.1, pp.90 - 103, 2018-07
ISSN	1073-449X
주제분야	General & Internal Medicine Respiratory System
저자 키워드	cell metabolism cancer vascular smooth muscle cells proliferation apoptosis
DOI	10.1164/rccm.201708-1751OC
자료유형
기관	UNIST

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학술활동

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Sox17 Deficiency Promotes Pulmonary Arterial Hypertension via HGF/c-Met Signaling POA(Pulse of Asia) 2021, 대한민국, 2021-07-02 ~ 2021-07-03

Sox17 deficiency promotes pulmonary arterial hypertension via HGF/c-Met signaling 2021 The 7th Gwangju-Boston Joint Cardiology Symposium, 대한민국, 2021-05-08 ~ 2021-05-08

Sox17 deficiency promotes pulmonary arterial hypertension 대한약리학회 추계학술대회, 대한민국, 2020-11-11 ~ 2020-11-12

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