Coagulation-independent effects of thrombin and Factor Xa: role of protease-activated receptors in pulmonary hypertension. Issue 16 (1st February 2022)

• Record Type: Journal Article
• Authors: Joseph, Christine; Berghausen, Eva Maria; Behringer, Arnica; Rauch, Bernhard; ten Freyhaus, Henrik; Gnatzy-Feik, Leoni Luisa; Krause, Max; Wong, Dickson W L; Boor, Peter; Baldus, Stephan; Vantler, Marius; Rosenkranz, Stephan
• Is Part Of: Cardiovascular research. Volume 118:Issue 16(2022)
• Page Start: 3225
• Page End: 3238
• Publication Date: 2022-02-01
• Subjects: Pulmonary hypertension -- Protease-activated receptors -- Factor Xa -- Thrombin; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Periodicals; 616.1
• DOI: 10.1093/cvr/cvac004
• Languages: English
• ISSNs: 0008-6363

Abstract

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. Graphical Abstract: