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Evidence for ANTXR2 as a therapeutic target on systemic-to-pulmonary shunt induced pulmonary arterial hypertension

Session Basic mechanisms of pulmonary disease

Speaker Xiaoyan Liu

Event : ESC Congress 2019

  • Topic : valvular, myocardial, pericardial, pulmonary, congenital heart disease
  • Sub-topic : Pulmonary Hypertension
  • Session type : Moderated Posters

Authors : XY Liu (Beijing,CN), LK Meng (Beijing,CN), W Yuan (Beijing,CN), ML Zheng (Beijing,CN), HJ Chi (Beijing,CN), XC Yang (Beijing,CN), J Li (Beijing,CN), JC Zhong (Beijing,CN)

Authors:
X.Y. Liu1 , L.K. Meng2 , W. Yuan1 , M.L. Zheng3 , H.J. Chi3 , X.C. Yang3 , J. Li3 , J.C. Zhong3 , 1Beijing Chaoyang Hospital, Capital Medical University, Medical Research Center - Beijing - China , 2Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, State Key Laboratory of Cardiovascular Disease - Beijing - China , 3Beijing Chaoyang Hospital, Capital Medical University, Heart Center & Beijing Key Laboratory of Hypertension Research - Beijing - China ,

On behalf: Medical Research Center, Beijing Chao-Yang Hospital

Topic(s):
Pulmonary Hypertension

Citation:
European Heart Journal ( 2019 ) 40 ( Supplement ), 3693

Introduction: Pulmonary arterial hypertension secondary to congenital heart disease (CHD-PAH) with systemic-to-pulmonary shunt is characterized by proliferative vascular remodeling. Excessive proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs) are the primary cellular bases of vascular remodeling. Anthrax toxin receptor 2 (ANTXR2) exhibits anti-proliferative properties. The effects of ANTXR2 on vascular remodeling and systemic-to-pulmonary shunt induced PAH remain unexplored.

Purpose: The purpose of this study was to determine the possible roles of ANTXR2 in the pathogenesis of systemic-to-pulmonary shunt induced PAH and explore its possible mechanisms.

Methods: Lung tissue sections from CHD-PAH patients, systemic-to-pulmonary shunt induced PAH rat model, ANTXR2−/− rats, and PASMCs were used. Immunohistochemistry, real time polymerase chain reaction, Western blot, proliferation, apoptosis, and next generation sequencing (NGS) were performed in this study.

Results: ANTXR2 expression was reduced in severe CHD-PAH patient lung tissue and pulmonary arterioles, as well as in lung tissues from rats with systemic-to-pulmonary shunt induced PAH. Over-expression of ANTXR2 in cultured PASMCs inhibited cell proliferation and promoted apoptosis, while knockdown of ANTXR2 promoted cell proliferation and inhibited apoptosis. Male ANTXR2−/− rats showed more severe percent medial thickness and muscularization of pulmonary arterioles than wild type (WT) rats in basal conditions, and exhibited heavier PAH following exposure to systemic-to-pulmonary shunt. To further determine the underling mechanism, NGS was performed in ANTXR2−/− rat lungs and that of WT littermates. A total of 1319 genes were found to be dysregulated, and biological processes influenced by these differentially expressed genes include negative regulation of blood vessel diameter,vasoconstriction, regulation of blood vessel diameter, regulation of blood vessel size, vascular process in circulatory system, etc.

Conclusion: Our work identifies a novel role for ANTXR2 in systemic-to-pulmonary shunt induced PAH based on the findings that ANTXR2 deficiency could exacerbate systemic-to- pulmonary shunt induced vascular remodeling in the development of PAH. ANTXR2 may be a potential target for CHD-PAH treatment.

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