On October 2, 2021, the group of pulmonary vascular disease from the lab published online an original research article entitled “Combination Treatment by HIF-2α Antagonist and P53 Agonist Reverses Established Pulmonary Hypertension” in British Journal of Pharmacology (impact factor: 8.739), a renowned journal in pharmacology. The research revealed that the combination of HIF-2α inhibitors and p53 agonists is a more efficient, safer, and precise treatment for pulmonary hypertension. Professor Wang Jian and Associate Professor Yang Kai from the lab are the co-corresponding authors of this article, and the co-first authors are 2019 PhD student Zheng Qiuyu, Professor Lu Wenju, and 2019 master student Yan Han.

The 2019 Nobel Prizes in Physiology or Medicine were awarded to three scientists from the United States and Britain, William G. Kaelin Jr, Sir Peter J. Ratcliffe and Gregg L. Semenza, on the basis of “discovering how cells perceive and adapt to the availability of oxygen”. Their groundbreaking discoveries revealed the mechanism of action of one of the most important adaptation in life, laying the foundation for us to understand how oxygen levels affect cell metabolism and physiological functions. The key molecules for cells to respond to hypoxic stimulation are hypoxia-inducible factors (HIFs). HIFs contain α subunit (HIF-1α and HIF-2α, and HIF-3α is only expressed in specific tissues) and β subunit (HIF-1β). HIF-α can form a dimer with HIF-β subunit to exert transcriptional activity. Under normal oxygen conditions, HIF-α subunits have poor stability and are easily degraded, and HIFs are in an inactive state; when the oxygen level decreases, the protease activity that mediates the degradation of HIF-α subunits decreases, which greatly improves the protein stability, forming dimers and exert transcriptional activity.

In hypoxia-related pulmonary hypertension, hypoxia-induced pulmonary vascular remodeling is the core mechanism leading to disease progression. In the early stage, Professor Wang Jian’s team and Nobel laureate Professor Gregg L. Semenza clarified that HIF-1α up-regulates the expression of human pulmonary artery smooth muscle cell BMP4 through transcription, which further activates the ERK/p38MAPK-TRPC1/6-SOCE signal axis and promotes the abnormal increase of the concentration of intracellular free calcium ions, leading to abnormal cell proliferation and migration, and promoting the occurrence and development of hypoxic pulmonary hypertension. Related results were published in Cardiovascular Research (impact factor: 10.787).

In this research, we first found that different HIF-α subtypes are specifically expressed in human pulmonary artery smooth muscle cells and endothelial cells, which have differential regulation of p53. Specifically: in human pulmonary artery endothelial cells, hypoxia induces a large accumulation of HIF-2α and mediates HIF-2α-dependent p53 up-regulation, which is an important incentive for the proliferation of endothelial cells; in human pulmonary artery smooth muscle cells, hypoxia induces the massive expression of HIF-1α, leading to p53 down-regulation and promoting the proliferation of smooth muscle cells. Recent studies have reported that specific HIF-2α inhibitors and p53 agonists can be used as new drugs for pulmonary hypertension to significantly alleviate the disease indications in animal models of pulmonary hypertension. However, in view of the specific expression of HIF-2α in endothelial cells, we analyzed that there may be a lacking of direct smooth-muscle targeting effects in HIF-2α inhibitors, while there may be pro-apoptotic side effects of undifferentiated endothelial cells in p53 agonists. Therefore, we speculated that the combination of the two can not only retain the protective effect of HIF-2α inhibitors in endothelial cells and the anti-smooth muscle proliferation effect of p53 agonists, but also minimize the apoptosis of endothelial cells induced by p53 agonists. We immediately verified this hypothesis through a series of animal models in vivo and in vitro cell model experiments, systematically demonstrated that the combination of HIF-2α inhibitors and p53 agonists is a more efficient, safer and precise treatment for pulmonary hypertension compared with the single-tablet treatment.