Parthenolide attenuates hypoxia-induced pulmonary hypertension through inhibiting STAT3 signaling

Yizhu Yao; Lanlan Song; Ziyi Zuo; Zhili Chen; Yijia Wang; Haijian Cai; Yanting Gu; Zhanghang Lv; Jiale Guan; Rujie Chen; Boxiang Wang; Lehe Yang; Xiaoying Huang; Liangxing Wang

doi:10.1016/j.phymed.2024.155976

Parthenolide attenuates hypoxia-induced pulmonary hypertension through inhibiting STAT3 signaling

Phytomedicine. 2024 Nov:134:155976. doi: 10.1016/j.phymed.2024.155976. Epub 2024 Aug 22.

Authors

Yizhu Yao¹, Lanlan Song¹, Ziyi Zuo¹, Zhili Chen¹, Yijia Wang¹, Haijian Cai¹, Yanting Gu¹, Zhanghang Lv¹, Jiale Guan², Rujie Chen², Boxiang Wang², Lehe Yang³, Xiaoying Huang⁴, Liangxing Wang⁵

Affiliations

¹ Pulmonary Division, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325035, China.
² The First Clinical Medical College, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China.
³ Pulmonary Division, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325035, China. Electronic address: yanglehe@wmu.edu.cn.
⁴ Pulmonary Division, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325035, China. Electronic address: huangxiaoying@wmu.edu.cn.
⁵ Pulmonary Division, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou Key Laboratory of Interdiscipline and Translational Medicine, Wenzhou Key Laboratory of Heart and Lung, Wenzhou, Zhejiang 325035, China. Electronic address: wangliangxing@wzhospital.cn.

PMID: 39265445
DOI: 10.1016/j.phymed.2024.155976

Abstract

Background: Pulmonary hypertension (PH) is a chronic lung disease characterized by the progressive pulmonary vascular remodeling with increased pulmonary arterial pressure and right ventricular failure. Pulmonary vascular remodeling involves the proliferation, migration, and resistance to apoptosis of pulmonary artery smooth cells (PASMCs). Parthenolide (PTN) is a bioactive compound derived from a traditional medical plant feverfew (Tanacetum parthenium), and it has been studied for treatment of pulmonary fibrosis, lung cancer, and other related ailments. However, the function of PTN in the treatment of PH has not been studied.

Purpose: This study aimed to evaluate the anti-proliferation and pro-apoptosis effects of PTN on PH and investigate its potential mechanisms.

Methods: An in vivo hypoxia-induced pulmonary hypertension (HPH) model was established by maintaining male rats in a hypoxia chamber (10% O₂) for 3 weeks, and PTN was intraperitoneally administered at the dose of 10 or 30 mg/kg. We assessed the impact of PTN on mean pulmonary arterial pressure (mPAP), pulmonary vascular remodeling, and right ventricular hypertrophy. In vitro, we evaluated hypoxia-induced cellular proliferation, migration, and apoptosis of rat PASMCs. Proteins related to the STAT3 signaling axis were analyzed by western blotting and immunofluorescence assays. Recovery experiments were performed using the STAT3 activator, colivelin TFA.

Results: PTN significantly alleviated the symptoms of HPH rats by attenuating pulmonary arterial remodeling. It also prevented the proliferation and migration of PASMCs. PTN also induced the apoptosis of PASMCs. PTN could directly interact with STAT3 and markedly inhibited STAT3 phosphorylation and nuclear translocation. In vitro, and in vivo experiments demonstrated that overexpression of STAT3 partially suppressed the effect of PTN.

Conclusion: Our study indicated that PTN alleviated hypoxia-induced pulmonary hypertension in rats by suppressing STAT3 activity.

Keywords: Apoptosis; Parthenolide; Proliferation; Pulmonary arterial hypertension; STAT3.

MeSH terms

Animals
Apoptosis* / drug effects
Cell Movement / drug effects
Cell Proliferation* / drug effects
Disease Models, Animal
Hypertension, Pulmonary* / drug therapy
Hypertrophy, Right Ventricular / drug therapy
Hypoxia* / complications
Hypoxia* / drug therapy
Male
Myocytes, Smooth Muscle / drug effects
Pulmonary Artery* / drug effects
Rats
Rats, Sprague-Dawley*
STAT3 Transcription Factor* / metabolism
Sesquiterpenes* / pharmacology
Signal Transduction* / drug effects
Tanacetum parthenium / chemistry
Vascular Remodeling* / drug effects

Substances

STAT3 Transcription Factor
Sesquiterpenes
parthenolide
Stat3 protein, rat