Apolipoprotein E Interrupts Interleukin-1β Signaling in Vascular Smooth Muscle Cells

Abstract

Objectives-Apolipoprotein E (apoE) exerts antiatherogenic effects but precise mechanisms remain unclear. We here investigated the effect of apoE on intracellular signaling by interleukin-1␤ (IL-1␤), a proinflammatory cytokine present in atherosclerotic lesions. Methods and Results-IL-1␤-induced expression and activation of inducible nitric oxide synthase and cyclooxygenase-2 were inhibited by apoE in vascular smooth muscle cells (VSMCs). These inhibitory effects were linked to the suppression of both NF-B and activating protein-1 (AP-1) transactivation, suggesting that the interruption of IL-1␤ signaling occurs upstream of transcription factors. Studies in VSMCs overexpressing IL-1␤ signaling intermediates revealed that NF-B transactivation was inhibited by apoE in MyD88-and IRAK1-but not in TRAF6-transfected cells. Furthermore, apoE prevented IRAK1 phosphorylation and IRAK1-TRAF6 but not MyD88-IRAK1 complex formation. Inhibitory effects of apoE on IL-1␤ signaling were abolished after silencing LDL receptor-related protein-1 (LRP1) expression with siRNA. In addition, inhibitors of adenylyl cyclase and protein kinase A (PKA) restored IL-1␤ signaling in apoE-treated VSMCs, whereas apoE stimulated PKA activity. ApoE inhibited VSMC activation in response to IL-18 but not to tumor necrosis factor-␣ or polyinosinic:polycytidylic acid. A polipoprotein E (apoE) is a major protein component of plasma lipoproteins and plays an important role in preventing atherosclerosis. The antiatherogenic effects of apoE are usually attributed to its ability to promote cholesterol efflux from peripheral cells for reverse cholesterol transport and to facilitate hepatic clearance of very low density lipoprotein (VLDL) and chylomicron remnants. However, apoE protects against atherosclerosis even in experimental settings, in which its effects on plasma cholesterol are negligible. For instance, transgenic expression of apoE in arterial wall led to inhibition of atheroma formation without affecting plasma lipoprotein profile. 1,2 Conversely, acceleration of atherosclerosis was observed in apoE ϩ/ϩ animals after transplantation of bone marrow from apoE-deficient mouse. 3 These results suggest that apoE directly inhibits the development of atherosclerosis in a manner independent of its role in cholesterol transport. Conclusion-ApoEAtherosclerosis is commonly regarded as a chronic inflammatory disease. Inflammation mediators such as cytokines and chemokines were shown to significantly contribute to the formation of atherosclerotic lesions, whereas antiinflammatory factors play the opposite role. ApoE has been previously suggested to suppress the expression of adhesion molecules on endothelial surface and thereby to prevent monocyte recruitment into the arterial intima. 4 However, little information is available concerning the involvement of apoE in initiation and perpetuation of inflammation within the vascular wall. In the present study, we examined the influence of apoE on cellular effects of interleukin-1␤ (IL-1␤), a proinflammatory cytok...

TRAF6-Mediated SM22α K21 Ubiquitination Promotes G6PD Activation and NADPH Production, Contributing to GSH Homeostasis and VSMC Survival In Vitro and In Vivo

“…35,36 Previous studies have demonstrated that TRAF6 deficiency reduces neointimal formation and remodeling after carotid artery ligation by inhibiting inflammatory cell infiltration and matrix degrading protease activity.…”

Apolipoprotein E and Peptide Mimetics Modulate Inflammation by Binding the SET Protein and Activating Protein Phosphatase 2A

“…This mechanism is also consistent with previous reports that 1) both the apoE [130][131][132][133][134][135][136][137][138][139][140][141][142][143][144][145][146][147][148][149] peptide and the apoE holoprotein bind to LRP (3,19); 2) apoE[133-149] can be detected inside cells (this paper), and the apoE holoprotein has also been found inside cells (37); 3) both apoE-mimetic peptides and apoE holoprotein inhibit production of NO, TNF-a, and other cytokines (15,16,18); and 4) both apoEmimetic peptides and apoE holoprotein reduce NF-kB activation through inhibition of IKK phosphorylation (20,21). These data, when coupled with the current demonstration that both the apoEmimetic peptides and the apoE holoprotein bind to SET, suggest that the peptides are true mimetics of the apoE protein in receptor binding and SET binding activities.…”

“…Clues to the molecular mechanism can be derived from the reports of Kawamura et al and Singh et al (20,21) Kawamura and coworkers (20) reported that the apoE holoprotein inhibits IL-1b signaling in vascular smooth muscle cells, resulting in reduced production of inflammatory mediators, including NO and PGE 2 . This effect was shown to be mediated through decreased phosphorylation and reduction of nuclear localized NF-kB leading to reduced production of inducible NO synthase (22).…”

Proteomic and Metabolomic Analysis of Smooth Muscle Cells Derived From the Arterial Media and Adventitial Progenitors of Apolipoprotein E–Deficient Mice

“…43 The increase in IL-18 transcription, as observed in the present study, is consistent with a recent report that apoE is a negative regulator of IL-18. 44 Overall, it is apparent that cytokines not only regulate immune or inflammatory responses in atherosclerosis but also contribute to glucose homeostasis 45 in the SMC compartment.…”