Integrin-mediated transcriptional activation of inhibitor of apoptosis proteins protects smooth muscle cells against apoptosis induced by degraded collagen

Apoptosis of smooth muscle cells (SMC) and degradation of the extracellular matrix (ECM) have both been implicated in atherosclerotic plaque rupture. We have previously reported that degraded type I collagen fragments induce a rapid but transient apoptotic burst initiated by calpains in SMC. The aim of the current study was to identify the pathway responsible for consecutive SMC survival. We show that exposure of SMC to collagen fragments resulted in a sustained activation of nuclear factor (NF)-\u3baB via phosphorylation and degradation of I\u3baB\u3b1. Its prevention through retroviral expression of superrepressor I\u3baB\u3b1 or proteasome inhibition potently induced apoptosis. In the presence of blocking antibodies to \u3b1v\u3b23 integrin and RGD peptides, collagen fragments no longer activated NF-\u3baB and apoptosis was enhanced. The mechanism by which NF-\u3baB was protecting SMC against collagen fragment-induced apoptosis was a transcriptional activation of several endogenous caspase inhibitors of the inhibitor of apoptosis protein (IAP) family as: (1) the expression of xIAP, c-IAP2, and survivin was potently induced by collagen fragments; (2) IAP expression was abrogated by superrepressor I\u3baB\u3b1; and (3) knockdown of each of the 3 IAPs by small interfering RNA (siRNA) resulted in enhanced apoptosis after collagen fragment treatment. Our data suggest that SMC exposed to degraded collagen are protected against apoptosis by a mechanism involving \u3b1v\u3b23-dependent NF-\u3baB activation with consequent activation of IAPs. This may constitute a novel antiapoptotic pathway ensuring SMC survival in settings of enhanced ECM degradation such as cell migration, vascular remodeling, and atherosclerotic plaque rupture

Degraded collagen fragments activate NF-kappa B and protect human smooth muscle cells against apoptosis through induction of inhibitor of apoptosis proteins (IAPs)

none3We report here that degraded type I collagen fragments activate NF-kappa B via phosphorylation and degradation of I kappa B alpha in human vascular smooth muscle cells (SMC) via alpha v beta 3 integrins. Simultanously, collagen fragments induce the expression of IAPs in a NF-kappa B-dependend manner. Inhibition of NF-kappa B results in suppression of IAP upregulation and induces apoptosis. These data identify a novel protective mechanism for SMC against apoptosis under conditions of enhanced extracellular matrix (ECM) degradation as e.g. in the atherosclerotic lesion.noneK. von Wnuck Lipinski; N. Ferri; B. LevkauK., von Wnuck Lipinski; Ferri, Nicola; B., Levka

Degraded collagen fragments activate NF-kappa B and protect human smooth muscle cells against apoptosis through induction of inhibitor of apoptosis proteins (IAPs)

We report here that degraded type I collagen fragments activate NF-kappa B via phosphorylation and degradation of I kappa B alpha in human vascular smooth muscle cells (SMC) via alpha v beta 3 integrins. Simultanously, collagen fragments induce the expression of IAPs in a NF-kappa B-dependend manner. Inhibition of NF-kappa B results in suppression of IAP upregulation and induces apoptosis. These data identify a novel protective mechanism for SMC against apoptosis under conditions of enhanced extracellular matrix (ECM) degradation as e.g. in the atherosclerotic lesion

Integrin-mediated transcriptional activation of inhibitor of apoptosis proteins protects smooth muscle cells against apoptosis induced by degraded collagen

Apoptosis of smooth muscle cells (SMC) and degradation of the extracellular matrix (ECM) have both been implicated in atherosclerotic plaque rupture. We have previously reported that degraded type I collagen fragments induce a rapid but transient apoptotic burst initiated by calpains in SMC. The aim of the current study was to identify the pathway responsible for consecutive SMC survival. We show that exposure of SMC to collagen fragments resulted in a sustained activation of nuclear factor (NF)-{kappa}B via phosphorylation and degradation of I{kappa}B{alpha}. Its prevention through retroviral expression of superrepressor I{kappa}B{alpha} or proteasome inhibition potently induced apoptosis. In the presence of blocking antibodies to {alpha}v f3 integrin and RGD peptides, collagen fragments no longer activated NF-{kappa}B and apoptosis was enhanced. The mechanism by which NF-{kappa}B was protecting SMC against collagen fragment-induced apoptosis was a transcriptional activation of several endogenous caspase inhibitors of the inhibitor of apoptosis protein (IAP) family as: (1) the expression of xIAP, c-IAP2, and survivin was potently induced by collagen fragments; (2) IAP expression was abrogated by superrepressor I{kappa}B{alpha}; and (3) knockdown of each of the 3 IAPs by small interfering RNA (siRNA) resulted in enhanced apoptosis after collagen fragment treatment. Our data suggest that SMC exposed to degraded collagen are protected against apoptosis by a mechanism involving {alpha}v f3-dependent NF-{kappa}B activation with consequent activation of IAPs. This may constitute a novel antiapoptotic pathway ensuring SMC survival in settings of enhanced ECM degradation such as cell migration, vascular remodeling, and atherosclerotic plaque rupture

Sphingosine-1-Phosphate (S1P) Lyase Inhibition Aggravates Atherosclerosis and Induces Plaque Rupture in ApoE−/−  Mice

Altered plasma sphingosine-1-phosphate (S1P) concentrations are associated with clinical manifestations of atherosclerosis. However, whether long-term elevation of endogenous S1P is pro- or anti-atherogenic remains unclear. Here, we addressed the impact of permanently high S1P levels on atherosclerosis in cholesterol-fed apolipoprotein E-deficient (ApoE−/−) mice over 12 weeks. This was achieved by pharmacological inhibition of the S1P-degrading enzyme S1P lyase with 4-deoxypyridoxine (DOP). DOP treatment dramatically accelerated atherosclerosis development, propagated predominantly unstable plaque phenotypes, and resulted in frequent plaque rupture with atherothrombosis. Macrophages from S1P lyase-inhibited or genetically deficient mice had a defect in cholesterol efflux to apolipoprotein A-I that was accompanied by profoundly downregulated cholesterol transporters ATP-binding cassette transporters ABCA1 and ABCG1. This was dependent on S1P signaling through S1PR3 and resulted in dramatically enhanced atherosclerosis in ApoE−/−/S1PR3−/− mice, where DOP treatment had no additional effect. Thus, high endogenous S1P levels promote atherosclerosis, compromise cholesterol efflux, and cause genuine plaque rupture