State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangdong Key Laboratory of Vascular Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University , Guangzhou , China.
Division of Translational and Regenerative Medicine , Tucson, Arizona.
Am J Physiol Lung Cell Mol Physiol. 2019 Jan 1;316(1):L216-L228. doi: 10.1152/ajplung.00538.2017. Epub 2018 Oct 25.
The tumor-suppressive role of p53, a transcription factor that regulates the expression of many genes, has been linked to cell cycle arrest, apoptosis, and senescence. The noncanonical function or the pathogenic role of p53 has more recently been implicated in pulmonary vascular disease. We previously reported that rapid nuclear accumulation of hypoxia-inducible factor (HIF)-1α in pulmonary arterial smooth muscle cells (PASMCs) upregulates transient receptor potential channels and enhances Ca entry to increase cytosolic Ca concentration ([Ca]). Also, we observed differences in HIF-1α/2α expression in PASMCs and pulmonary arterial endothelial cells (PAECs). Here we report that p53 is increased in PAECs, but decreased in PASMCs, isolated from mice with hypoxia-induced pulmonary hypertension (PH) and rats with monocrotaline (MCT)-induced PH (MCT-PH). The increased p53 in PAECs from rats with MCT-PH is associated with an increased ratio of Bax/Bcl-2, while the decreased p53 in PASMCs is associated with an increased HIF-1α. Furthermore, p53 is downregulated in PASMCs isolated from patients with idiopathic pulmonary arterial hypertension compared with PASMCs from normal subjects. Overexpression of p53 in normal PASMCs inhibits store-operated Ca entry (SOCE) induced by passive depletion of intracellularly stored Ca in the sarcoplasmic reticulum, while downregulation of p53 enhances SOCE. These data indicate that differentially regulated expression of p53 and HIF-1α/2α in PASMCs and PAECs and the cross talk between p53 and HIF-1α/2α in PASMCs and PAECs may play an important role in the development of PH via, at least in part, induction of PAEC apoptosis and PASMC proliferation.
p53 作为一种转录因子，可调节许多基因的表达，其抑癌作用与细胞周期停滞、细胞凋亡和衰老有关。最近，p53 的非典型功能或致病作用被牵连到肺血管疾病中。我们之前曾报道，低氧诱导因子 (HIF)-1α 在肺动脉平滑肌细胞（PASMCs）中的快速核积累上调瞬时受体电位通道并增强钙内流，以增加细胞浆钙浓度([Ca])。此外，我们观察到 PASMCs 和肺动脉内皮细胞（PAECs）中 HIF-1α/2α 的表达存在差异。在这里，我们报告在由缺氧诱导的肺动脉高压（PH）的小鼠和由单环酸（MCT）诱导的 PH（MCT-PH）的大鼠中分离的 PAECs 中 p53 增加，而在 PASMCs 中 p53 减少。MCT-PH 大鼠的 PAECs 中 p53 的增加与 Bax/Bcl-2 比值增加有关，而 PASMCs 中 p53 的减少与 HIF-1α 增加有关。此外，与正常受试者的 PASMCs 相比，特发性肺动脉高压患者的 PASMCs 中 p53 表达下调。p53 在正常 PASMCs 中的过表达抑制由肌浆网内储存 Ca 被动耗竭诱导的储存操作 Ca 内流（SOCE），而 p53 的下调增强 SOCE。这些数据表明，PASMCs 和 PAECs 中 p53 和 HIF-1α/2α 的差异表达以及 PASMCs 和 PAECs 中 p53 和 HIF-1α/2α 之间的串扰可能通过至少部分诱导 PAEC 凋亡和 PASMC 增殖，在 PH 的发展中发挥重要作用。
