Oxidative stress regulates IGF1R expression in vascular smooth-muscle cells via p53 and HDAC recruitment

Abstract

Apoptosis of VSMCs (vascular smooth-muscle cells) leads to features of atherosclerotic plaque instability. We have demonstrated previously that plaque-derived VSMCs have reduced IGF1 (insulin-like growth factor 1) signalling, resulting from a decrease in the expression of IGF1R (IGF1 receptor) compared with normal aortic VSMCs [Patel, Zhang, Siddle, Soos, Goddard, Weissberg and Bennett (2001) Circ. Res. 88, [895][896][897][898][899][900][901][902]. In the present study, we show that apoptosis induced by oxidative stress is inhibited by ectopic expression of IGF1R. Oxidative stress repressed IGF1R expression at multiple levels, and this was also blocked by mutant p53. Oxidative stress also induced p53 phosphorylation and apoptosis in VSMCs. p53 negatively regulated IGF1R promoter activity and expression and, consistent with this, p53 −/− VSMCs demonstrated increased IGF1R expression, both in vitro and in advanced atherosclerotic plaques in vivo. Oxidativestress-induced interaction of endogenous p53 with TBP (TATAbox-binding protein) was dependent on p53 phosphorylation. Oxidative stress also increased the association of p53 with HDAC1 (histone deacetylase 1). Trichostatin A, a specific HDAC inhibitor, or p300 overexpression relieved the repression of IGF1R following oxidative stress. Furthermore, acetylated histone-4 association with the IGF1R promoter was reduced in cells subjected to oxidative stress. These results suggest that oxidativestress-induced repression of IGF1R is mediated by the association of phosphorylated p53 with the IGF1R promoter via TBP, and by the subsequent recruitment of chromatin-modifying proteins, such as HDAC1, to the IGF1R promoter-TBP-p53 complex.

Akt Regulates the Survival of Vascular Smooth Muscle Cells via Inhibition of FoxO3a and GSK3

“…The lower level of IGF1R expression in pVSMCs in vitro (4,7) and in intimal VSMCs in plaques (11) and oxidized low density lipoprotein-dependent down-regula-tion of IGF1R (27,28) correlates with their increased susceptibility to apoptosis. It is possible that the decrease in progression of atherosclerosis in ApoE Ϫ/Ϫ mice in response to infusion of IGF1 (29) is, at least partly, due to increased survival of VSMCs, especially since loss of VSMC promotes features of advanced plaques (1).…”

“…Mediates Survival of VSMCs-Previously, we demonstrated that VSMCs derived from human plaques (pVSMCs) express lower levels of IGF1R when compared with VSMCs derived from normal human aortas (4,7). pVSMCs also show reduced proliferation and increased sensitivity to apoptosis (3,4).…”

“…pVSMCs also show reduced proliferation and increased sensitivity to apoptosis (3,4). Ectopic expression of IGF1R in VSMCs increases the rate of proliferation and markedly reduces apoptosis (7,22). Although there is a good correlation between reduced IGF1R expression and reduction in proliferation and survival in pVSMCs, a causative effect has not been established.…”

“…Oxidative stress is increasingly implicated in the development of atherosclerosis (5) and increased oxidative damage, and elevated levels of DNA strand breaks occur in human atherosclerotic plaques (6). Oxidative stress reduces IGF1R expression and induces VSMC apoptosis in culture (7)(8)(9)(10). Reduced IGF1R expression is also seen within plaques, suggesting that IGF1R-dependent survival regulates apoptosis in vivo (11,12).…”

Angiotensin II–Inducible Smooth Muscle Cell Apoptosis Involves the Angiotensin II Type 2 Receptor, GATA-6 Activation, and FasL-Fas Engagement

“…For example, we recently showed that TSA relieves repression of IGF1R following oxidative stress. 42 TSA also upregulates the expression of angiostatic extracellular metalloproteinase ADAMTS1. 43 Conversely, TSA can suppress tissue factor induction by tumor necrosis factor ␣, lipopolysaccharide, and interleukin-1␤ in vascular endothelial cells.…”