Inactivation of p53 Is Sufficient to Induce Development of Pulmonary Hypertension in Rats.
Inactivation of p53 Is Sufficient to Induce Development of Pulmonary Hypertension in Rats.
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DOI：
10.1371/journal.pone.0131940
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Eddahibi S
中科院分区：
文献类型：
--
作者：
Jacquin S;Rincheval V;Mignotte B;Richard S;Humbert M;Mercier O;Londoño-Vallejo A;Fadel E;Eddahibi S
肺动脉高压（PAH）中的肺动脉平滑肌细胞（PA-SMCs）与癌细胞有相似之处。由于p53的生长抑制和促凋亡作用及其在癌症中的失活，我们假设p53通路在PAH中可以改变。因此，我们探索了p53在野百合碱（MCT）大鼠肺动脉高压（PH）模型中的参与，以及p53失活对pifithrin-α（PFT，一种p53活性抑制剂）动物处理的病理生理学后果。通过肺动脉压、右心室肥厚和动脉壁厚度评估PH的发展。Western blot检测MCT和PFT对肺组织p53通路表达的影响。与单次注射MCT（60 mg/kg）相似，每日PFT给药（2.2 mg/kg/天）14天，诱导PH并加重MCT诱导的PH。在MCT给药后第一周和PH发生前，p53、p21和MDM 2蛋白水平显著降低;而PFT给药有效改变了p53靶蛋白水平。TUNEL和MTT法检测PFT对培养的人肺动脉平滑肌细胞的抗凋亡和促增殖作用。p53的药理学失活足以通过PFT的慢性治疗诱导PH，这是与其抗凋亡和促增殖特性相关的作用。在大鼠MCT模型中，p53通路在第一周内下调。这些体内实验表明，p53通路在PH发病的起始阶段。
Pulmonary artery smooth muscle cells (PA-SMCs) in pulmonary arterial hypertension (PAH) show similarities to cancer cells. Due to the growth-suppressive and pro-apoptotic effects of p53 and its inactivation in cancer, we hypothesized that the p53 pathway could be altered in PAH. We therefore explored the involvement of p53 in the monocrotaline (MCT) rat model of pulmonary hypertension (PH) and the pathophysiological consequences of p53 inactivation in response to animal treatment with pifithrin-α (PFT, an inhibitor of p53 activity). PH development was assessed by pulmonary arterial pressure, right ventricular hypertrophy and arterial wall thickness. The effect of MCT and PFT on lung p53 pathway expression was evaluated by western blot. Fourteen days of daily PFT treatment (2.2 mg/kg/day), similar to a single injection of MCT (60 mg/kg), induced PH and aggravated MCT-induced PH. In the first week after MCT administration and prior to PH development, p53, p21 and MDM2 protein levels were significantly reduced; whereas PFT administration effectively altered the protein level of p53 targets. Anti-apoptotic and pro-proliferative effects of PFT were revealed by TUNEL and MTT assays on cultured human PA-SMCs treated with 50 μM PFT. Pharmacological inactivation of p53 is sufficient to induce PH with a chronic treatment by PFT, an effect related to its anti-apoptotic and pro-proliferative properties. The p53 pathway was down-regulated during the first week in the rat MCT model. These in vivo experiments implicate the p53 pathway at the initiation stages of PH pathogenesis.
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DOI：
10.1164/rccm.200709-1369pp
发表时间：
2008-09-15
影响因子：
24.7
作者：
Rai, Pradeep R.;Cool, Carlyne D.;Voelkel, Norbert F.
通讯作者：
Voelkel, Norbert F.
影响因子：
24
作者：
Humbert, M;Morrell, NW;Rabinovitch, M
通讯作者：
Rabinovitch, M
影响因子：
56.9
作者：
Vassilev, LT;Vu, BT;Liu, EA
通讯作者：
Liu, EA
影响因子：
15.9
作者：
McMurtry, MS;Archer, SL;Michelakis, ED
通讯作者：
Michelakis, ED
影响因子：
15.9
作者：
Eddahibi, S;Humbert, M;Adnot, S
通讯作者：
Adnot, S