PAI-1 Deficiency Drives Pulmonary Vascular Smooth Muscle Remodeling and Pulmonary Hypertension.

التفاصيل البيبلوغرافية
العنوان:	PAI-1 Deficiency Drives Pulmonary Vascular Smooth Muscle Remodeling and Pulmonary Hypertension.
المؤلفون:	Kudryashova TV; University of Pittsburgh, Pittsburgh, PA, United States., Zaitsev SV; Children's Hospital of Philadelphia, Philadelphia, PA, United States., Jiang L; University of California Davis Medical Center, Davis, CA, United States., Buckley BJ; University of Wollongong, Wollongong, NSW, Australia., McGuckin JP; Drexel University, Philadelphia, PA, United States., Goncharov D; University of California Davis Medical Center, Davis, CA, United States., Zhyvylo I; University of California Davis Medical Center, Davis, CA, United States., Lin D; University of California Davis Medical Center, Davis, CA, United States., Newcomb G; The Ohio State University Wexner Medical Center, Columbus, OH, United States., Piper B; The Ohio State University Wexner Medical Center, Columbus, OH, United States., Bogamuwa S; The Ohio State University Wexner Medical Center, Columbus, OH, United States., Saiyed A; University of California Davis Medical Center, Columbus, OH, United States., Teos L; University of California Davis Medical Center, Davis, CA, United States., Pena A; University of Pittsburgh, Pittsburgh, PA, United States., Ranson M; University of Wollongong, Wollongong, NSW, Australia., Greenland JR; University of California, San Francisco, San Francisco, CA, United States., Wolters PJ; Department of Medicine, University of California, San Francisco, San Francisco, CA, United States., Kelso MJ; University of Wollongong, Wollongong, NSW, Australia., Poncz M; Children's Hospital of Philadelphia, Philadelphia, PA, United States., DeLisser HM; Department of Medicine, University of Pennsylvania, Philadelphia, PA, United States., Cines DB; Department of Pathology, University of Pennsylvania, Philadelphia, PA, United States., Goncharova EA; University of California Davis Medical Center, Davis, CA, United States., Farkas L; The Ohio State University Wexner Medical Center, Columbus, OH, United States., Stepanova V; Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States.
المصدر:	American journal of physiology. Lung cellular and molecular physiology [Am J Physiol Lung Cell Mol Physiol] 2024 Jun 11. Date of Electronic Publication: 2024 Jun 11.
Publication Model:	Ahead of Print
نوع المنشور:	Journal Article
اللغة:	English
بيانات الدورية:	Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901229 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1504 (Electronic) Linking ISSN: 10400605 NLM ISO Abbreviation: Am J Physiol Lung Cell Mol Physiol Subsets: MEDLINE
أسماء مطبوعة:	Original Publication: Bethesda, MD : American Physiological Society, c1989-
مستخلص:	Pulmonary arterial hypertension (PAH) is a progressive disease characterized by vasoconstriction and remodeling of small pulmonary arteries (PAs). Central to the remodeling process is a switch of pulmonary vascular cells to a proliferative, apoptosis-resistant phenotype. Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of urokinase-type and tissue-type plasminogen activators (uPA and tPA), but its role in PAH is unsettled. Here, we report that: (1) PAI-1 is deficient in remodeled small PAs and in early-passage PA smooth muscle and endothelial cells (PASMCs and PAECs) from subjects with PAH compared to controls; (2) PAI-1 ^-/- mice spontaneously develop pulmonary vascular remodeling associated with up-regulation of mTORC1 signaling, pulmonary hypertension (PH), and right ventricle (RV) hypertrophy; and (3) pharmacological inhibition of uPA in human PAH PASMCs suppresses pro-proliferative mTORC1 and SMAD3 signaling, restores PAI-1 levels, reduces proliferation and induces apoptosis in vitro , and prevents the development of SU5416/hypoxia-induced PH and RV hypertrophy in vivo in mice. These data strongly suggest that down-regulation of PAI-1 in small PAs promotes vascular remodeling and PH due to unopposed activation of uPA and consequent up-regulation of mTOR and TGF-b signaling in PASMCs, and call for further studies to determine the potential benefits of targeting the PAI-1/uPA imbalance to attenuate and/or reverse pulmonary vascular remodeling and PH.
التعليقات:	Update of: bioRxiv. 2023 Sep 22:2023.09.21.558893. doi: 10.1101/2023.09.21.558893. (PMID: 37790328)
معلومات مُعتمدة:	R01HL150638 HHS \| NIH \| National Heart, Lung, and Blood Institute (NHLBI); Nina Ireland Program for Lung Health UCSF \| Department of Medicine, University of California, San Francisco (UCSF Department of Medicine); R24 HL123767 United States HL NHLBI NIH HHS; R35HL150698 HHS \| NIH \| National Heart, Lung, and Blood Institute (NHLBI); R01 HL130261 United States HL NHLBI NIH HHS; R01HL130261 HHS \| NIH \| National Heart, Lung, and Blood Institute (NHLBI); RO1HL141462 HHS \| NIH \| National Heart, Lung, and Blood Institute (NHLBI); R01HL166932 HHS \| NIH \| National Heart, Lung, and Blood Institute (NHLBI); LAM0139P07-19 LAM Foundation (TheLAMFoundation); R01HL139881 HHS \| NIH \| National Heart, Lung, and Blood Institute (NHLBI); APP1181179 DHAC \| National Health and Medical Research Council (NHMRC); TS150032 DOD \| USA \| MEDCOM \| MRDC \| U.S. Army Medical Research Acquisition Activity (USAMRAA); CX002011 ORD \| Clinical Science Research and Development (CSRD); Cardiovascular Medical Research and Education Fund (CMREF); RO1HL159256 HHS \| NIH \| National Heart, Lung, and Blood Institute (NHLBI); R01HL172488 HHS \| NIH \| National Heart, Lung, and Blood Institute (NHLBI); R01 HL150638 United States HL NHLBI NIH HHS; R01 HL172488 United States HL NHLBI NIH HHS
فهرسة مساهمة:	Keywords: plasminogen activator inhibitor (PAI-1)); pulmonary hypertension; urokinase PA (uPA)
تواريخ الأحداث:	Date Created: 20240611 Latest Revision: 20240624
رمز التحديث:	20240624
DOI:	10.1152/ajplung.00110.2024
PMID:	38860847
قاعدة البيانات:	MEDLINE

الوصف
تدمد:	1522-1504
DOI:	10.1152/ajplung.00110.2024