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

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.

• Authors: 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
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 179 Issue 5 Pg. 1065-1081 (03 2022) ISSN: 1476-5381 [Electronic] England
• PMID: 34599843 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The British Pharmacological Society.

Chemical References

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

Topics

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