Blockade of JAK2 protects mice against hypoxia‐induced pulmonary arterial hypertension by repressing pulmonary arterial smooth muscle cell proliferation

AbstractObjectivesHypoxia 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.

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Published: Jan 14, 2020
Vol/Issue: 53(2)
License: View

Authors

L

Lei Zhang

Key Laboratory of Organ Transplantation NHC Key Laboratory of Organ Transplantation Key Laboratory of Organ Transplantation Ministry of Education The Center for Biomedical Research, Chinese Academy of Medical Sciences Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China; Department of Respiratory and Critical Care Medicine Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China

Y

Yi Wang

Key Laboratory of Organ Transplantation NHC Key Laboratory of Organ Transplantation Key Laboratory of Organ Transplantation Ministry of Education The Center for Biomedical Research, Chinese Academy of Medical Sciences Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China; Department of Respiratory and Critical Care Medicine Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China

G

Guorao Wu

Key Laboratory of Organ Transplantation NHC Key Laboratory of Organ Transplantation Key Laboratory of Organ Transplantation Ministry of Education The Center for Biomedical Research, Chinese Academy of Medical Sciences Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China; Department of Respiratory and Critical Care Medicine Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China

L

Lizong Rao

Key Laboratory of Organ Transplantation NHC Key Laboratory of Organ Transplantation Key Laboratory of Organ Transplantation Ministry of Education The Center for Biomedical Research, Chinese Academy of Medical Sciences Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China; Department of Respiratory and Critical Care Medicine Affiliated Hospital of Guilin Medical University Guilin China

Y

Yanqiu Wei

Key Laboratory of Organ Transplantation NHC Key Laboratory of Organ Transplantation Key Laboratory of Organ Transplantation Ministry of Education The Center for Biomedical Research, Chinese Academy of Medical Sciences Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China; Department of Respiratory and Critical Care Medicine Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China

H

Huihui Yue

Key Laboratory of Organ Transplantation NHC Key Laboratory of Organ Transplantation Key Laboratory of Organ Transplantation Ministry of Education The Center for Biomedical Research, Chinese Academy of Medical Sciences Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China; Department of Respiratory and Critical Care Medicine Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China

T

Ting Yuan

Key Laboratory of Organ Transplantation NHC Key Laboratory of Organ Transplantation Key Laboratory of Organ Transplantation Ministry of Education The Center for Biomedical Research, Chinese Academy of Medical Sciences Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China; Department of Respiratory and Critical Care Medicine Affiliated Hospital of Guilin Medical University Guilin China

P

PING YANG

Key Laboratory of Organ Transplantation NHC Key Laboratory of Organ Transplantation Key Laboratory of Organ Transplantation Ministry of Education The Center for Biomedical Research, Chinese Academy of Medical Sciences Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China

F

Fei Xiong

Key Laboratory of Organ Transplantation NHC Key Laboratory of Organ Transplantation Key Laboratory of Organ Transplantation Ministry of Education The Center for Biomedical Research, Chinese Academy of Medical Sciences Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China

S

Shu Zhang

Key Laboratory of Organ Transplantation NHC Key Laboratory of Organ Transplantation Key Laboratory of Organ Transplantation Ministry of Education The Center for Biomedical Research, Chinese Academy of Medical Sciences Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China

Q

Qing Zhou

Key Laboratory of Organ Transplantation NHC Key Laboratory of Organ Transplantation Key Laboratory of Organ Transplantation Ministry of Education The Center for Biomedical Research, Chinese Academy of Medical Sciences Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China

Z

Zhishui Chen

Key Laboratory of Organ Transplantation NHC Key Laboratory of Organ Transplantation Key Laboratory of Organ Transplantation Ministry of Education The Center for Biomedical Research, Chinese Academy of Medical Sciences Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China

J

Jinxiu Li

Shenzhen Third People's Hospital Shenzhen China

B

Bi‐Wen Mo

Department of Respiratory and Critical Care Medicine Affiliated Hospital of Guilin Medical University Guilin China

H

Huilan Zhang

Key Laboratory of Organ Transplantation NHC Key Laboratory of Organ Transplantation Key Laboratory of Organ Transplantation Ministry of Education The Center for Biomedical Research, Chinese Academy of Medical Sciences Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China; Department of Respiratory and Critical Care Medicine Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China

W

Weining Xiong

Key Laboratory of Organ Transplantation NHC Key Laboratory of Organ Transplantation Key Laboratory of Organ Transplantation Ministry of Education The Center for Biomedical Research, Chinese Academy of Medical Sciences Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China; Department of Respiratory and Critical Care Medicine Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China; Department of Respiratory Medicine Shanghai Ninth People's Hospital Shanghai Jiaotong University School of Medicine Shanghai China

C

Cong‐Yi Wang

Key Laboratory of Organ Transplantation NHC Key Laboratory of Organ Transplantation Key Laboratory of Organ Transplantation Ministry of Education The Center for Biomedical Research, Chinese Academy of Medical Sciences Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China

Funding

National Natural Science Foundation of China Award: 81530024

Ministry of Science and Technology Award: 2016YFC1305002

Huazhong University of Science and Technology

Cite This Article

Lei Zhang, Yi Wang, Guorao Wu, et al. (2020). Blockade of JAK2 protects mice against hypoxia‐induced pulmonary arterial hypertension by repressing pulmonary arterial smooth muscle cell proliferation. Cell Proliferation, 53(2). https://doi.org/10.1111/cpr.12742

Blockade of JAK2 protects mice against hypoxia‐induced pulmonary arterial hypertension by repressing pulmonary arterial smooth muscle cell proliferation

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