Combination Treatment by HIF-2α Antagonist and P53 Agonist Reverses Established Pulmonary Hypertension.

AIMS The tumor suppressor p53 is distinctly regulated in pulmonary arterial smooth muscle cells (PASMC) and endothelial cells (PAEC) in patients and animals with pulmonary hypertension (PH). Emerging studies reported therapeutic effects of monotreatment by either p53 agonists or hypoxia inducible factor 2α (HIF-2α) antagonists for the treatment of PH. Objective of this study is to investigate whether combined treatment of p53 agonist, Nutlin3a, and HIF-2α antagonist, PT2385, confers advanced efficacy than monotreatment strategies, based on a cell type-divergent regulation. METHODS AND RESULTS SU5416/hypoxia-induced PH (SuHx-PH) rat model was used as in vivo animal model, and cultured human PASMC and PAEC were used as in vitro cell models. Results showed the hypoxia-induced proliferation of PASMC is associated with decreased p53, while the hypoxia-induced PAEC apoptosis is associated with increased p53, in a HIF-2α dependent mechanism. Combined treatment of Nutlin3a with PT2385 (PT2385+Nutlin3a) confers advanced efficacy by simultaneously inhibiting the hypoxia-induced PASMC proliferation and PAEC apoptosis, overcoming the shortages of monotreatment that: 1) Nutlin3a exacerbates hypoxia-induced PAEC apoptosis due to the induction of p53 in PAEC (EC-p53); 2) PT2385 inhibits the PAEC apoptosis since HIF-2α is predominantly expressed in PAEC, but lacks direct effect on the hypoxia-induced PASMC proliferation. Furthermore, comparing to monotreatment, combination treatment represents advanced efficacy to reverse established SuHx-PH, especially in the protection of PA vasculature, by normalizing the smooth muscle thickening, protecting endothelial damage and function. CONCLUSION Combination treatment confers advanced therapeutic efficacy against PH through a precise modulation of p53 and HIF-2α in PASMC and PAEC.