Established pulmonary hypertension in rats was reversed by a combination of a HIF-2α antagonist and a p53 agonist.
Established pulmonary hypertension in rats was reversed by a combination of a HIF-2α antagonist and a p53 agonist.
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HIF-2α 拮抗剂和 p53 激动剂的组合可逆转大鼠中已形成的肺动脉高压
DOI：
10.1111/bph.15696
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发表时间：
2021
影响因子：
7.3
通讯作者：
Wang Jian
中科院分区：
文献类型：
--
作者：
Zheng Qiuyu;Lu Wenju;Yan Han;Duan Xin;Chen Yuqin;Zhang Chenting;Luo Xiaoyun;Chen Jiyuan;Wang Chao;Liu Shiyun;Li Yi;Tang Haiyang;Rahimi Shamin;Rahimi Shayan;Yuan Jason X-J;Zhong Nanshan;Yang Kai;Wang Jian
背景与目的最近的研究报道了肿瘤抑制因子P53(P53)激动剂或缺氧诱导因子2α(HIF-2α)拮抗剂单一治疗对肺动脉高压(PH)的疗效。本研究基于p53激动剂Nutlin3a和HIF-2α拮抗剂PT2385对P53在Ph患者和动物的细胞类型分化调节作用的研究，探讨P53激动剂Nutlin3a和HIF-2受体拮抗剂PT2385联合治疗P53是否比单用更有效。结果低氧诱导的PASMC增殖与P53的降低有关，而低氧诱导的血管内皮细胞的凋亡与P53的升高有关，这是通过HIF-2α依赖的机制实现的。Nutlin3a和PT2385联合治疗可同时抑制缺氧诱导的PASMC增殖和PAEC的凋亡，克服了单一治疗的副作用。这些结果是：(I)Nutlin3a通过诱导细胞内P53的表达而加重缺氧诱导的血管内皮细胞的凋亡；(Ii)PT2385抑制血管内皮细胞的凋亡，因为缺氧诱导的血管内皮细胞主要表达HIF-2α，但对缺氧诱导的血管内皮细胞增殖没有直接作用。结论：联合用药通过选择性调节PASMC和PAEC中P53和HIF-2α的表达，对大鼠肺泡巨噬细胞和肺血管内皮细胞中P53和HIF-2的表达具有更好的治疗作用。
Background and PurposeRecent 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 ApproachThe 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 ResultsHypoxia‐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 ImplicationsCombination treatment confers greater therapeutic efficacy against PH through a selective modulation of p53 and HIF‐2α in PASMC and PAEC.