Universität zu Köln

Joseph, Christine ORCID: 0000-0002-7447-7341, Berghausen, Eva Maria, Behringer, Arnica, Rauch, Bernhard ORCID: 0000-0002-6003-4662, Ten Freyhaus, Henrik, Gnatzy-Feik, Leoni Luisa, Krause, Maximilian, Wong, Dickson W. L., Boor, Peter ORCID: 0000-0001-9921-4284, Baldus, Stephan, Vantler, Marius and Rosenkranz, Stephan (2022). Coagulation-independent effects of thrombin and Factor Xa: role of protease-activated receptors in pulmonary hypertension. Cardiovasc. Res., 118 (16). S. 3225 - 3239. OXFORD: OXFORD UNIV PRESS. ISSN 1755-3245

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Abstract

Aims Pulmonary arterial hypertension (PAH) is a devastating disease with limited therapeutic options. Vascular remodelling of pulmonary arteries, characterized by increased proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs), is a hallmark of PAH. Here, we aimed to systematically characterize coagulation-independent effects of key coagulation proteases thrombin and Factor Xa (FXa) and their designated receptors, protease-activated receptor (PAR)-1 and -2, on PASMCs in vitro and experimental PAH in vivo. Methods and results In human and murine PASMCs, both thrombin and FXa were identified as potent mitogens, and chemoattractants. FXa mediated its responses via PAR-1 and PAR-2, whereas thrombin signalled through PAR-1. Extracellular-signal regulated kinases 1/2, protein kinase B (AKT), and sphingosine kinase 1 were identified as downstream mediators of PAR-1 and PAR-2. Inhibition of FXa or thrombin blunted cellular responses in vitro, but unexpectedly failed to protect against hypoxia-induced PAH in vivo. However, pharmacological inhibition as well as genetic deficiency of both PAR-1 and PAR-2 significantly reduced vascular muscularization of small pulmonary arteries, diminished right ventricular systolic pressure, and right ventricular hypertrophy upon chronic hypoxia compared to wild-type controls. Conclusion Our findings indicate a coagulation-independent pathogenic potential of thrombin and FXa for pulmonary vascular remodelling via acting through PAR-1 and PAR-2, respectively. While inhibition of single coagulation proteases was ineffective in preventing experimental PAH, our results propose a crucial role for PAR-1 and PAR-2 in its pathobiology, thus identifying PARs but not their dedicated activators FXa and thrombin as suitable targets for the treatment of PAH.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Joseph, Christine UNSPECIFIED orcid.org/0000-0002-7447-7341 UNSPECIFIED Berghausen, Eva Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Behringer, Arnica UNSPECIFIED UNSPECIFIED UNSPECIFIED Rauch, Bernhard UNSPECIFIED orcid.org/0000-0002-6003-4662 UNSPECIFIED Ten Freyhaus, Henrik UNSPECIFIED UNSPECIFIED UNSPECIFIED Gnatzy-Feik, Leoni Luisa UNSPECIFIED UNSPECIFIED UNSPECIFIED Krause, Maximilian UNSPECIFIED UNSPECIFIED UNSPECIFIED Wong, Dickson W. L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Boor, Peter UNSPECIFIED orcid.org/0000-0001-9921-4284 UNSPECIFIED Baldus, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED Vantler, Marius UNSPECIFIED UNSPECIFIED UNSPECIFIED Rosenkranz, Stephan UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-676624
DOI:	10.1093/cvr/cvac004
Journal or Publication Title:	Cardiovasc. Res.
Volume:	118
Number:	16
Page Range:	S. 3225 - 3239
Date:	2022
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1755-3245
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INFLAMMATION; MODEL; MECHANISMS Multiple languages Cardiac & Cardiovascular Systems Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/67662