Effects of p53-knockout in vascular smooth muscle cells on atherosclerosis in mice

Abstract

In vitro and in vivo evidence has indicated that the tumor suppressor, p53, may play a significant role in the regulation of atherosclerotic plaque formation. In vivo studies using global knockout mice models, however, have generated inconclusive results that do not address the roles of p53 in various cell types involved in atherosclerosis. In this study, we have specifically ablated p53 in vascular smooth muscle cells (VSMC) in the ApoE-/- mouse model to investigate the roles of p53 in VSMC in atherosclerotic plaque formation and stability. We found that p53 deficiency in VSMC alone did not affect the overall size of atherosclerotic lesions. However, there was a significant increase in the number of p53-/- VSMC in the fibrous caps of atherosclerotic plaques in the early stages of plaque development. Loss of p53 results in migration of VSMC at a faster rate using wound healing assays and augments PDGF-induced formation of circular dorsal ruffles (CDR), known to be involved in cell migration and internalization of surface receptors. Furthermore, aortic VSMC from ApoE-/- /p53-/- mice produce significantly more podosomes and are more invasive. We conclude that p53-/- VSMC are enriched in the fibrous caps of lesions at early stages of plaque formation, which is caused in part by an increase in VSMC migration and invasion as shown by p53-/- VSMC in culture having significantly higher rates of migration and producing more CDRs and invasive podosomes.

Cytokine‐induced apoptosis inhibitor 1 (CIAPIN1) accelerates vascular remodelling via p53 and JAK2‐STAT3 regulation in vascular smooth muscle cells

“…The role of p53 in regulating cell cycle progression and invasion is well known (Mak, 2011;Muller & Vousden, 2014). A number of studies have reported the anti-proliferative and anti-migrative roles of p53 in atherosclerosis (Cao et al, 2017;Guevara et al, 2001;Matsushita et al, 2000;Scheinman et al, 1999), and TP53 transcription is tightly regulated in the cell cycle progression (Boggs & Reisman, 2006;S. Wang & El-Deiry, 2006).…”

P53 in the impaired lungs

“…Atherosclerosis is the result of vascular inflammation. P53 deficiency affected the vascular smooth muscle cell migration and proliferation, an indication of atherosclerotic lesion formation [ 116 ].…”

Silencing of long non-coding RNA H19 downregulates CTCF to protect against atherosclerosis by upregulating PKD1 expression in ApoE knockout mice

“…TIMPs are endogenous protein regulators of the MMP family [30], promoting TIMP-2 expression contributes to retarded recruitment of monocytes to inflammatory sites including atherosclerotic plaques, interruption in intraplaque activity of MMP and facilitated stabilization of atherosclerotic plaque lesions [31]. Moreover, p53 has also been highlighted as a significant regulator of atherosclerotic plaque formation [32]. Knockdown of H19 has been revealed to inhibit glioma-induced angiogenesis and glioma-associated endothelial cell capabilities of proliferation, migration and tube formation by decreasing the expression of angiogenic factor vasohibin 2 through upregulation of miR-29a [33].…”