Review
The p53 pathway in vasculature revisited: A therapeutic target for pathological vascular remodeling?

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Abstract

Pathological vascular remodeling contributes to the development of restenosis following intraluminal interventions, transplant vasculopathy, and pulmonary arterial hypertension. Activation of the tumor suppressor p53 may counteract vascular remodeling by inhibiting aberrant proliferation of vascular smooth muscle cells and repressing vascular inflammation. In particular, the development of different lines of small-molecule p53 activators ignites the hope of treating remodeling-associated vascular diseases by targeting p53 pharmacologically. In this review, we discuss the relationships between p53 and pathological vascular remodeling, and summarize current experimental data suggesting that drugging the p53 pathway may represent a novel strategy to prevent the development of vascular remodeling.

Introduction

The tumor suppressor protein p53 is encoded by the TP53 gene, which was discovered over 40 years ago in transformed malignant cells [1]. Mutations in p53 are related to about 50% of human cancers [2]. Despite the well documented roles of p53 in tumorigenesis, this protein is ubiquitously expressed and is thought to have major impacts on the physiology and/or pathophysiology of virtually all organs in the body, because it is a key transcription factor implicated in modulating the expression of ~60 genes involved in various very fundamental aspects of cell biology, including cell cycle arrest, apoptosis, cell senescence, and DNA repair [1], [3], [4]. Unsurprisingly, numerous studies have illustrated a tight link between p53 and the cardiovascular system [5]. In the heart, aberrant activation of the p53 pathway promotes the pathogenesis of various cardiac diseases, such as infarction-induced cardiac remodeling, hypertrophic and dilated cardiomyopathy, and chemotherapy-induced cardiotoxicity, all of which may result in heart failure [5]. In blood vessels, p53 is activated in atherosclerotic plaques, and is involved in regulating growth arrest, cell senescence and apoptosis of vascular smooth muscle cells (VSMCs) [6]. However, deletion of p53 gene in VSMCs appears to have no significant effect on atherogenesis [7]. In contrast, evidence suggests that the endogenous p53 protein expressed in macrophages has a protective role against the development of atherosclerosis [8], [9]. On the other hand, overexpression of p53 in the plaque may induce detrimental effects by promoting plaque destabilization [10]. Several studies have revealed that the inhibitory effect of p53 on VSMC proliferation can repress the development of pathological vascular remodeling caused by vascular injuries [11], [12]. This property of p53 in vascular remodeling is of a special translational interest currently, due to the emergence of novel small molecule activators of the p53 pathway [2]. Preclinical experiments in various animal models have suggested that drugging the p53 pathway may represent a promising strategy to prevent the development of pathological vascular remodeling with different etiologies. Here we summarize our current knowledge of the relationship between p53 and vascular remodeling, with a highlight on the emerging evidence demonstrating potential therapeutic efficacies of small molecule p53 activators.

Section snippets

Overview of the major mechanisms responsible for p53 activation

The p53 pathway is activated under various stress conditions, exemplified by genotoxic stress (DNA damages), oxidative stress, hypoxia, and nutrient depletion, which among others are mostly relevant to vascular cells [1], [13] (see Fig. 1). Of note, p53 is a short lived protein in cells. The ubiquitin ligase Mdm2 induces ubiquitination and degradation of the p53 protein in unstressed cells. Such stress stimuli can dissociate p53 from Mdm2, likely via Mdm2 dephosphorylation, leading to p53

Major cellular outcomes downstream of p53 activation

Activation of the p53 pathway promotes cell cycle arrest, cell senescence, and apoptosis [1] (Fig. 1). Induction of cell cycle arrest by p53 is attributable to transcriptional upregulation of several key cell cycle regulators including p21CIP1/WAF1, GADD45, and 14–3–3 proteins [23]. p21CIP1/WAF1 contributes to G1/S as well as G2/M blockade by inhibiting the functions of different cyclin/CDK complexes. GADD45 promotes G2/M arrest mainly by repressing the activity of cyclin B. On the other hand,

Development of small molecule activators of the p53 pathway

Because of the exceptional importance of p53 in repressing tumorigenesis, great efforts have been invested in identifying small molecule p53 activators, which are expected to be efficacious for treating cancers (reviewed in [2], [30], [31], [32]). Different targeting strategies have been explored to achieve this goal (see Fig. 1). Firstly, disruption of the interaction between p53 and its negative regulator Mdm2 causes stabilization and accumulation of wild type p53. Nutlins are a series of

Roles of p53 in pathological vascular remodeling and effects of p53 activating agents

Pathological remodeling of the vessel wall contributes to the development of several proliferative vascular diseases, including arterial restenosis, transplant vasculopathy (TV), and pulmonary arterial hypertension (PAH). Emerging evidence supports that activation of the p53 pathway has beneficial effects on vascular remodeling, primarily by repressing VSMC proliferation and vascular inflammation (see Fig. 2). In line with this notion, pre-clinical studies have revealed therapeutic effects of

p53 and vascular inflammation

In addition to VSMC activation, vascular inflammation is another equally important factor in advancing the remodeling process, regardless of the underlying etiologies [54], [55], [56], [57], [70], [73], [74], [75], [111], [112], [113]. The inflammatory reaction mediated by perivascular (adventitial) macrophages appears to be a key contributor, especially in the early phase of vascular inflammation [114]. Macrophage infiltration in the adventitia occurs early after angioplastic injury [115], and

Would p53 activation induce cell apoptosis in normal vascular cells?

It is a concern whether activation of the p53 pathway triggers apoptosis in normal vascular cells. Different studies have suggested that arterial VSMCs are fairly insensitive to p53-induced apoptosis. Overexpression of wild type p53 alone in arterial VSMCs does not induce apoptosis, whereas the pro-apoptotic activity of p53 is only observed in the presence of an additional apoptosis stimulus such as doxorubicin [59] or UV irradiation [60]. Instead, p53 primarily induces cell cycle arrest in

Perspectives on the translational value of small molecule p53 activators

One of the most concerning issues about the translational value of small molecule p53 activators is whether these agents would induce unwanted cell cycle arrest in normally proliferating cells (for example hematopoietic stem cells) [31]. Indeed, phase I clinical trials with RG7112 (a nutlin analogue) have shown that neutropenia and thrombocytopenia are among the observed adverse events [146], [147], although none of the cases of death were considered to be related to drug side effects. However,

Conflict of interest declaration

None.

Acknowledgements

This work was supported partially by the following grants: National Natural Science Foundation of China (82070265 and 81770469 for F.J.), Key Research and Development Program of Shandong Province (2019GSF108052 for X.C.), and National Science and Technology Program of China (2012ZX09303016-003 for H.G.).

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