The role of p53 in the alternation of vascular functions

Abstract

Ageing is a risk factor for many degenerative diseases. Cardiovascular diseases (CVDs) are usually big burdens for elderly, caregivers and the health system. During the aging process, normal functions of vascular cells and tissue progressively lost and eventually develop vascular diseases. Endothelial dysfunction, reduced bioavailability of endothelium-derived nitric oxide are usual phenomena observed in patients with cardiovascular diseases. Myriad of studies have been done to investigate to delay the vascular dysfunction or improve the vascular function to prolong the aging process. Tumor suppressor gene p53, also a transcription factor, act as a gatekeeper to regulate a number of genes to maintain normal cell function including but not limited to cell proliferation, cell apoptosis. p53 also crosstalk with other key transcription factors like hypoxia-inducible factor 1 alpha that contribute to the progression of cardiovascular diseases. Therefore, in recent three decades, p53 has drawn scientists' attention on its effects in vascular function. Though the role of tumor suppressor gene p53 is still not clear in vascular function, it is found to play regulatory roles and may involve in vascular remodeling, atherosclerosis or pulmonary hypertension. p53 may have a divergent role in endothelial and vascular muscle cells in those conditions. In this review, we describe the different effects of p53 in cardiovascular physiology. Further studies on the effects of endothelial cell-specific p53 deficiency on atherosclerotic plaque formation in common animal models are required before the therapeutic potential can be realized.

Keywords: atherosclerosis; endothelial dysfunction; p53; vascular smooth muscle cell; vascular smooth muscle migration; vascular smooth muscle proliferation.

FIGURE 1

Overview on posttranslational modifications of p53 under stress stimulus. In normal condition, MDM2 and MDM4 promotes p53 ubiquitination leading to p53 degradation in proteasome. Under stress stimulus, sirtuin 1 is activated and deacetylate p53 at K382, 379, 320 or 373 for promoting p53 transcription, PACF and p300/CBP is also activated to promote p53 transcription via acetylation at k305, 370, 372, 373, 381, 282, 386 or 164. Ubiquitin proteasome of p53 degradation is inhibited via repression MDM2 and MDM4 binding to p53 by stress stimulated phosphorylation of p53 at ser 15, 20, and thr18 (Created with BioRender.com).

FIGURE 2

The development of normal endothelial cell (EC) to senescent EC. In normal situation, sirt 1, Klotho and fibroblast growth factor 21, etc., give protective effects on normal endothelial cells, preventing senescence. In senescent EC, expression of p53 was upregulated with a reduction of endothelial nitric oxide production.