Established pulmonary hypertension in rats was reversed by a combination of a HIF-2α antagonist and a p53 agonist

Qiuyu Zheng; Wenju Lu; Han Yan; Xin Duan; Yuqin Chen; Chenting Zhang; Xiaoyun Luo; Jiyuan Chen; Chao Wang; Shiyun Liu; Yi Li; Haiyang Tang; Shamin Rahimi; Shayan Rahimi; Jason X-J Yuan; Nanshan Zhong; Kai Yang; Jian Wang

doi:10.1111/bph.15696

Established pulmonary hypertension in rats was reversed by a combination of a HIF-2α antagonist and a p53 agonist

Br J Pharmacol. 2022 Mar;179(5):1065-1081. doi: 10.1111/bph.15696. Epub 2021 Nov 16.

Authors

Qiuyu Zheng^{1

2}, Wenju Lu¹, Han Yan¹, Xin Duan³, Yuqin Chen¹, Chenting Zhang¹, Xiaoyun Luo¹, Jiyuan Chen¹, Chao Wang¹, Shiyun Liu¹, Yi Li¹, Haiyang Tang¹, Shamin Rahimi², Shayan Rahimi², Jason X-J Yuan², Nanshan Zhong¹, Kai Yang¹, Jian Wang^{1

2}

Affiliations

¹ State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
² Section of Physiology, Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of California, San Diego, La Jolla, California, USA.
³ State Key Laboratory of Cardiovascular Disease, Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.

PMID: 34599843
DOI: 10.1111/bph.15696

Abstract

Background and purpose: Recent studies reported therapeutic effects of monotherapy with either tumour suppressor p53 (p53) agonist or hypoxia-inducible factor 2α (HIF-2α) antagonist for pulmonary hypertension (PH). This study investigated whether a combined treatment of p53 agonist, Nutlin3a, and HIF-2α antagonist, PT2385, would be more effective than monotherapy, based on the cell type-divergent regulation of p53 in pulmonary arterial smooth muscle cells (PASMC) and endothelial cells (PAEC) in patients and animals with PH.

Experimental approach: The SU5416/hypoxia-induced PH (SuHx-PH) rat model was used, along with cultured human PASMC and PAEC. Western blot, RT-PCR, siRNA and immunohistochemical methods were used along with echocardiography and studies with isolated pulmonary arteries.

Key results: Hypoxia-induced proliferation of PASMC is associated with decreased p53, whereas hypoxia-induced PAEC apoptosis is associated with increased p53, via a HIF-2α-dependent mechanism. Combined treatment with Nutlin3a and PT2385 is more effective by simultaneously inhibiting the hypoxia-induced PASMC proliferation and PAEC apoptosis, overcoming the side-effects of monotherapy. These are (i) Nutlin3a exacerbates hypoxia-induced PAEC apoptosis by inducing p53 in PAEC and (ii) PT2385 inhibits PAEC apoptosis because HIF-2α is predominantly expressed in PAEC but lacks direct effects on the hypoxia-induced PASMC proliferation. In rats, combination treatment is more effective than monotherapy in reversing established SuHx-PH, especially in protecting pulmonary arterial vasculature, by normalizing smooth muscle thickening, protecting against endothelial damage and improving function.

Conclusion and implications: Combination treatment confers greater therapeutic efficacy against PH through a selective modulation of p53 and HIF-2α in PASMC and PAEC.

Keywords: Nutlin3a; PT2385; combination therapy; endothelial cell; hypoxia-inducible factor 2α; p53; pulmonary hypertension; smooth muscle cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Basic Helix-Loop-Helix Transcription Factors* / antagonists & inhibitors
Cell Proliferation
Cells, Cultured
Endothelial Cells / metabolism
Humans
Hypertension, Pulmonary* / pathology
Hypoxia / complications
Hypoxia / drug therapy
Myocytes, Smooth Muscle
Pulmonary Artery
Rats
Tumor Suppressor Protein p53* / agonists

Substances

Basic Helix-Loop-Helix Transcription Factors
Tumor Suppressor Protein p53
endothelial PAS domain-containing protein 1