Abstract
ObjectivesHypoxia is an important risk factor for pulmonary arterial remodelling in pulmonary arterial hypertension (PAH), and the Janus kinase 2 (JAK2) is believed to be involved in this process. In the present report, we aimed to investigate the role of JAK2 in vascular smooth muscle cells during the course of PAH.MethodsSmooth muscle cell (SMC)‐specific Jak2 deficient mice and their littermate controls were subjected to normobaric normoxic or hypoxic (10% O2) challenges for 28 days to monitor the development of PAH, respectively. To further elucidate the potential mechanisms whereby JAK2 influences pulmonary vascular remodelling, a selective JAK2 inhibitor was applied to pre‐treat human pulmonary arterial smooth muscle cells (HPASMCs) for 1 hour followed by 24‐hour hypoxic exposure.ResultsMice with hypoxia‐induced PAH were characterized by the altered JAK2/STAT3 activity in pulmonary artery smooth muscle cells. Therefore, induction of Jak2 deficiency in SMCs protected mice from hypoxia‐induced increase of right ventricular systolic pressure (RVSP), right ventricular hypertrophy and pulmonary vascular remodelling. Particularly, loss of Jak2 significantly attenuated chronic hypoxia‐induced PASMC proliferation in the lungs. Similarly, blockade of JAK2 by its inhibitor, TG‐101348, suppressed hypoxia‐induced human PASMC proliferation. Upon hypoxia‐induced activation, JAK2 phosphorylated signal transducer and activator of transcription 3 (STAT3), which then bound to the CCNA2 promoter to transcribe cyclin A2 expression, thereby promoting PASMC proliferation.ConclusionsOur studies support that JAK2 could be a culprit contributing to the pulmonary vascular remodelling, and therefore, it could be a viable target for prevention and treatment of PAH in clinical settings.
Highlights
Pulmonary arterial hypertension (PAH) is a life-threatening disease manifested by the progressive pulmonary vascular remodelling, which results in persistently increased pulmonary arterial pressure, eventually culminating in right heart failure.[1,2]
A great deal of effort has been recently devoted to dissecting the pathoaetiologies underlying PAH, the exact molecular mechanisms, remain poorly understood
There is emerging evidence that Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signalling is activated during PAH initiation and progression
Summary
Pulmonary arterial hypertension (PAH) is a life-threatening disease manifested by the progressive pulmonary vascular remodelling, which results in persistently increased pulmonary arterial pressure, eventually culminating in right heart failure.[1,2] Sustained pulmonary vasoconstriction and vascular remodelling characterized by the concentric wall thickening and lumen obliteration of small- and medium-sized pulmonary arteries (PAs), are the major causes of elevated pulmonary vascular resistance and pulmonary arterial pressure in patients with PAH.[3]. There is compelling evidence that pulmonary arterial smooth muscle cell (PASMC) hyperplasia is a cardinal feature of pulmonary vascular remodelling that underlies the development and progression of PAH.[4,5]. The functional importance of JAK2 in systemic arterial vascular smooth muscle cells (VSMCs) has been noted,[18] but its role in VSMCs during the course of pulmonary blood vessel remodelling is yet to be clarified. To address this question, we generated a SMC-specific Jak[2] knockout model and demonstrated that Jak[2] deficiency in SMCs protected mice from hypoxia-induced PAH and substantially reduced right ventricular systolic pressure (RVSP), the right ventricle/left ventricle plus septum [RV/ (LV+S)] weight ratio and the median width of pulmonary arterioles. Our data support that strategies aimed at inhibiting JAK2 activity could be a viable treatment for PAH in clinical settings
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