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

Ziyi Wang, Kai Yang, Qiuyu Zheng, Chenting Zhang, Haiyang Tang, Aleksandra Babicheva, Qian Jiang, Meichan Li, Yuqin Chen, Shane G. Carr, Kang Wu, Qian Zhang, Angela Balistrieri, Christina Wang, Shanshan Song, Ramon J. Ayon, Ankit Desai, Stephen M. Black, Joe GN Garcia, Ayako Makino & 3 others Jason Yuan, Wenju Lu, Jian Wang

Research output: Contribution to journalArticle

Abstract

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 Ca2+ entry to increase cytosolic Ca2+ concentration ([Ca2+]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 Ca2+ entry (SOCE) induced by passive depletion of intracellularly stored Ca2+ 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.

Original languageEnglish (US)
Pages (from-to)L216-L228
JournalAmerican journal of physiology. Lung cellular and molecular physiology
Volume316
Issue number1
DOIs
StatePublished - Jan 1 2019

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Pulmonary Hypertension
Smooth Muscle Myocytes
Lung
Hypoxia-Inducible Factor 1
Endothelial Cells
Monocrotaline
Down-Regulation
Apoptosis
Transient Receptor Potential Channels
Sarcoplasmic Reticulum
Cell Cycle Checkpoints
Vascular Diseases
Lung Diseases
Transcription Factors
Up-Regulation

Keywords

  • Bcl-2 proteins
  • endothelial cell apoptosis
  • p53
  • smooth muscle cell proliferation
  • tumor-suppressor gene

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

Cite this

Divergent changes of p53 in pulmonary arterial endothelial and smooth muscle cells involved in the development of pulmonary hypertension. / 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; Black, Stephen M.; Garcia, Joe GN; Makino, Ayako; Yuan, Jason; Lu, Wenju; Wang, Jian.

In: American journal of physiology. Lung cellular and molecular physiology, Vol. 316, No. 1, 01.01.2019, p. L216-L228.

Research output: Contribution to journalArticle

Wang, Z, Yang, K, Zheng, Q, Zhang, C, Tang, H, Babicheva, A, Jiang, Q, Li, M, Chen, Y, Carr, SG, Wu, K, Zhang, Q, Balistrieri, A, Wang, C, Song, S, Ayon, RJ, Desai, A, Black, SM, Garcia, JGN, Makino, A, Yuan, J, Lu, W & Wang, J 2019, 'Divergent changes of p53 in pulmonary arterial endothelial and smooth muscle cells involved in the development of pulmonary hypertension', American journal of physiology. Lung cellular and molecular physiology, vol. 316, no. 1, pp. L216-L228. https://doi.org/10.1152/ajplung.00538.2017
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 ; Black, Stephen M. ; Garcia, Joe GN ; Makino, Ayako ; Yuan, Jason ; Lu, Wenju ; Wang, Jian. / Divergent changes of p53 in pulmonary arterial endothelial and smooth muscle cells involved in the development of pulmonary hypertension. In: American journal of physiology. Lung cellular and molecular physiology. 2019 ; Vol. 316, No. 1. pp. L216-L228.
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AU - Tang, Haiyang

AU - Babicheva, Aleksandra

AU - Jiang, Qian

AU - Li, Meichan

AU - Chen, Yuqin

AU - Carr, Shane G.

AU - Wu, Kang

AU - Zhang, Qian

AU - Balistrieri, Angela

AU - Wang, Christina

AU - Song, Shanshan

AU - Ayon, Ramon J.

AU - Desai, Ankit

AU - Black, Stephen M.

AU - Garcia, Joe GN

AU - Makino, Ayako

AU - Yuan, Jason

AU - Lu, Wenju

AU - Wang, Jian

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