Divergent changes of p53 in pulmonary arterial endothelial and smooth muscle cells involved in the development of pulmonary hypertension

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 316; no. 1; pp. L216 - L228
• Main Authors: Wang, Ziyi, Yang, Kai, Zheng, Qiuyu, Zhang, Chenting, Tang, Haiyang, Babicheva, Aleksandra, Jiang, Qian, Li, Meichan, Chen, Yuqin, Carr, Shane G., Wu, Kang, Zhang, Qian, Balistrieri, Angela, Wang, Christina, Song, Shanshan, Ayon, Ramon J., Desai, Ankit A., Black, Stephen M., Garcia, Joe G. N., Makino, Ayako, Yuan, Jason X.-J., Lu, Wenju, Wang, Jian
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.01.2019
• Subjects: Animals; Apoptosis; Basic Helix-Loop-Helix Transcription Factors - metabolism; Bcl-2 protein; bcl-2-Associated X Protein - metabolism; Calcium (reticular); Calcium - metabolism; Calcium channels; Calcium influx; Calcium ions; Cell cycle; Cell Proliferation; Cells; Crosstalk; Depletion; Endothelial cells; Endothelial Cells - metabolism; Endothelial Cells - pathology; Gene expression; Hypertension; Hypertension, Pulmonary - etiology; Hypertension, Pulmonary - metabolism; Hypertension, Pulmonary - pathology; Hypoxia; Hypoxia - complications; Hypoxia - metabolism; Hypoxia - pathology; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Hypoxia-inducible factors; Lung diseases; Male; Mice; Monocrotaline; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Muscles; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; p53 Protein; Proteins; Proto-Oncogene Proteins c-bcl-2 - metabolism; Pulmonary arteries; Pulmonary Artery - metabolism; Pulmonary Artery - pathology; Pulmonary hypertension; Sarcoplasmic reticulum; Sarcoplasmic Reticulum - metabolism; Sarcoplasmic Reticulum - pathology; Senescence; Smooth muscle; Transient receptor potential proteins; Tumor Suppressor Protein p53 - metabolism; Vascular diseases; smooth muscle cell proliferation; Bcl-2 proteins; tumor-suppressor gene; endothelial cell apoptosis; p53
• ISSN: 1040-0605; 1522-1504; 1522-1504
• DOI: 10.1152/ajplung.00538.2017

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 2+ entry to increase cytosolic Ca 2+ concentration ([Ca 2+ ] cyt ). 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 2+ entry (SOCE) induced by passive depletion of intracellularly stored Ca 2+ 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.