PAR-2 Inhibition Reverses Experimental Pulmonary Hypertension

Abstract

Rationale: A hallmark of the vascular remodeling process underlying pulmonary hypertension (PH) is the aberrant proliferation and migration of pulmonary arterial smooth muscle cells (PASMC). Accumulating evidence suggests that mast cell mediators play a role in the pathogenesis of PH.Objective: In the present study we investigated the importance of protease-activated receptor (PAR)-2 and its ligand mast cell tryptase in the development of PH. Methods and Results:Our results revealed strong increase in PAR-2 and tryptase expression in the lungs of idiopathic pulmonary arterial hypertension (IPAH) patients, hypoxia-exposed mice, and monocrotaline (MCT)-treated rats. Elevated tryptase levels were also detected in plasma samples from IPAH patients. Hypoxia and platelet-derived growth factor (PDGF)-BB upregulated PAR-2 expression in PASMC. This effect was reversed by HIF (hypoxia inducible factor)-1␣ depletion, PDGF-BB neutralizing antibody, or the PDGF-BB receptor antagonist Imatinib. Attenuation of PAR-2 expression was also observed in smooth muscle cells of pulmonary vessels of mice exposed to hypoxia and rats challenged with MCT in response to Imatinib treatment. Tryptase induced PASMC proliferation and migration as well as enhanced synthesis of fibronectin and matrix metalloproteinase-2 in a PAR-2-and ERK1/2-dependent manner, suggesting that PAR-2-dependent signaling contributes to vascular remodeling by various mechanisms. Furthermore, PAR-2 ؊/؊ mice were protected against hypoxia-induced PH, and PAR-2 antagonist application reversed established PH in the hypoxia mouse model. Key Words: pulmonary arterial hypertension Ⅲ protease-activated receptor-2 Ⅲ mast cells P ulmonary hypertension (PH) is characterized by a persistent increase in pulmonary arterial pressure, which can ultimately lead to right ventricular failure and death. Factors that contribute to the increased vascular resistance in PH include vasoconstriction, vascular remodeling, and thrombosis. 1 Pulmonary vasoconstriction can result from the imbalance of vasoactive mediators such as nitric oxide, endothelin-1, prostacyclin, and serotonin. Another potent stimulator of arterial contraction is alveolar hypoxia. Low oxygen levels down-regulate voltage-gated potassium channels, leading to depolarization of smooth muscle cells (SMC), subsequent Ca 2ϩ influx, and vasoconstriction. [2][3][4] Prolonged contraction stimulates the proliferation and migration of SMC and fibroblasts leading to medial or adventitial thickening of the pulmonary arteries. 1 Remodeling can also be triggered by a dysfunction of endothelial cells, thereby altering vascular homeostasis by changing cytokine/growth factor levels and procoagulant potential. 1 Vascular damage and endothelial dysfunction can alter the composition of the extracellular matrix by the induction of matrix metalloproteinases (MMPs), resulting in SMC migration and proliferation. 5 Accumulating evidence suggests that inflammatory cells may play an active role in the development of PH. 6,7 The number of mast cells...

Thrombin Has Biphasic Effects on the Nitric Oxide-cGMP Pathway in Endothelial Cells and Contributes to Experimental Pulmonary Hypertension

“…In addition, previous data indicate that thrombin induced a sustained contraction in normal pulmonary arteries by activating PAR-1 [63]. Recently, data were published that indicate a role for PAR-2 expressed on vascular smooth muscle cells in vascular remodeling in pulmonary hypertension [64].…”

Differential contribution of FXa and thrombin to vascular inflammation in a mouse model of sickle cell disease

“…47 Recent studies demonstrated that rivaroxaban treatment, as well as PAR-2 or IL-6 deficiency, attenuates PH in animal models. [48][49][50] Also, there is at least 1 case report in which PH For personal use only. on May 10, 2018. by guest www.bloodjournal.org From improved in a patient treated with an IL-6 receptor-blocking antibody.…”

Compartment-specific expression of collagens and their processing enzymes in intrapulmonary arteries of IPAH patients

“…For real-time PCR analyses, samples from n ϭ 8 donors and n ϭ 6 -10 IPAH were investigated. Three of 10 utilized IPAH lungs have been previously reported (28). These patients' characteristics are reported in Table 1.…”