Berghausen, Eva M., Janssen, Wiebke, Vantler, Marius, Gnatzy-Feik, Leoni L., Krause, Max, Behringer, Arnica, Joseph, Christine, Zierden, Mario ORCID: 0000-0002-5169-751X, ten Freyhaus, Henrik, Klinke, Anna, Baldus, Stephan, Alcazar, Miguel A., Savai, Rajkumar, Pullamsetti, Soni Savai, Wong, Dickson W. L., Boor, Peter, Zhao, Jean J., Schermuly, Ralph T. and Rosenkranz, Stephan (2021). Disrupted PI3K subunit p110 alpha signaling protects against pulmonary hypertension and reverses established disease in rodents. J. Clin. Invest., 131 (19). ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 1558-8238

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Abstract

Enhanced signaling via RTKs in pulmonary hypertension (PH) impedes current treatment options because it perpetuates proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs). Here, we demonstrated hyperphosphorylation of multiple RTKs in diseased human vessels and increased activation of their common downstream effector phosphatidylinositol 3 '-kinase (PI3K), which thus emerged as an attractive therapeutic target. Systematic characterization of class IA catalytic PI3K isoforms identified p110 alpha as the key regulator of pathogenic signaling pathways and PASMC responses (proliferation, migration, survival) downstream of multiple RTKs. Smooth muscle cell-specific genetic ablation or pharmacological inhibition of p110 alpha prevented onset and progression of pulmonary hypertension (PH) as well as right heart hypertrophy in vivo and even reversed established vascular remodeling and PH in various animal models. These effects were attributable to both inhibition of vascular proliferation and induction of apoptosis. Since this pathway is abundantly activated in human disease, p110 alpha represents a central target in PH.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Berghausen, Eva M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Janssen, WiebkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vantler, MariusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gnatzy-Feik, Leoni L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krause, MaxUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Behringer, ArnicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Joseph, ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zierden, MarioUNSPECIFIEDorcid.org/0000-0002-5169-751XUNSPECIFIED
ten Freyhaus, HenrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klinke, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baldus, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alcazar, Miguel A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Savai, RajkumarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pullamsetti, Soni SavaiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wong, Dickson W. L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Boor, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zhao, Jean J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schermuly, Ralph T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosenkranz, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-597833
DOI: 10.1172/JCI136939
Journal or Publication Title: J. Clin. Invest.
Volume: 131
Number: 19
Date: 2021
Publisher: AMER SOC CLINICAL INVESTIGATION INC
Place of Publication: ANN ARBOR
ISSN: 1558-8238
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
FORKHEAD TRANSCRIPTION FACTORS; MUSCLE-CELL PROLIFERATION; ARTERIAL-HYPERTENSION; PHOSPHATIDYLINOSITOL 3-KINASE; DELETION; PTEN; IDENTIFICATION; MECHANISMS; INHIBITION; IMATINIBMultiple languages
Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/59783

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