Coagulation-independent effects of thrombin and Factor Xa: role of protease-activated receptors in pulmonary hypertension

被引:8
|
作者
Joseph, Christine [1 ,2 ]
Berghausen, Eva Maria [1 ,2 ]
Behringer, Arnica [1 ,2 ]
Rauch, Bernhard [3 ]
Ten Freyhaus, Henrik [1 ,2 ]
Gnatzy-Feik, Leoni Luisa [1 ,2 ,4 ]
Krause, Maximilian [1 ,2 ,4 ]
Wong, Dickson W. L. [5 ]
Boor, Peter [5 ]
Baldus, Stephan [1 ,2 ,4 ]
Vantler, Marius [1 ,2 ]
Rosenkranz, Stephan [1 ,2 ,4 ]
机构
[1] Univ Cologne, Klin Innere Med 3, Kerpener Str 62, D-50937 Cologne, Germany
[2] Univ Cologne, Ctr Mol Med Cologne CMMC, Robert Koch Str 21, D-50931 Cologne, Germany
[3] Univ Greifswald, Inst Pharmakol, Felix Hausdorff Str 3, D-17487 Greifswald, Germany
[4] Univ Cologne, Cologne Cardiovasc Res Ctr CCRC, Kerpener Str 62, D-50937 Cologne, Germany
[5] RWTH Aachen Univ Hosp, Inst Pathol, Pauwelsstr 30, D-52074 Aachen, Germany
关键词
Pulmonary hypertension; Protease-activated receptors; Factor Xa; Thrombin; INFLAMMATION; MODEL; MECHANISMS;
D O I
10.1093/cvr/cvac004
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
引用
收藏
页码:3225 / 3238
页数:14
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