TRAF3IP2 mediates atherosclerotic plaque development and vulnerability in ApoE −/− mice

Abstract

Background and aims Atherosclerosis is a major cause of heart attack and stroke. Inflammation plays a critical role in the development of atherosclerosis. Since the cytoplasmic adaptor molecule TRAF3IP2 (TRAF3-Interacting Protein 2) plays a causal role in various autoimmune and inflammatory diseases, we hypothesized that TRAF3IP2 mediates atherosclerotic plaque development. Methods TRAF3IP2/ApoE double knockout (DKO) mice were generated by crossing TRAF3IP2−/− and ApoE−/− mice. ApoE−/− mice served as controls. Both DKO and control mice were fed a high-fat diet for 12 weeks. Plasma lipids were measured by ELISA, atherosclerosis by en face analysis of aorta and plaque cross-section measurements at the aortic valve region, plaque necrotic core area, collagen and smooth muscle cell content by histomorphometry, and aortic gene expression by RT-qPCR. Results The plasma lipoprotein profile was not altered by TRAF3IP2 gene deletion in ApoE−/− mice. While total aortic plaque area was decreased in DKO female, but not male mice, the plaque necrotic area was significantly decreased in DKO mice of both genders. Plaque collagen and smooth muscle cell contents were increased significantly in both female and male DKO mice compared to respective controls. Aortic expression of proinflammatory cytokine (Tumor necrosis factor α, TNFα), chemokine (Chemokine (C-X-C motif) Ligand 1, CXCL1) and adhesion molecule (Vascular cell adhesion molecule 1, VCAM1; and Intercellular adhesion molecule 1, ICAM1) gene expression were decreased in both male and female DKO mice. In addition, the male DKO mice showed a markedly reduced expression of extracellular matrix (ECM)-related genes, including TIMP1 (Tissue inhibitor of metalloproteinase 1), RECK (Reversion-Inducing- Cysteine-Rich Protein with Kazal Motifs) and ADAM17 (A Disintegrin And Metalloproteinase 17). Conclusions TRAF3IP2 plays a causal role in atherosclerotic plaque development and vulnerability, possibly by inducing the expression of multiple proinflammatory mediators. TRAF3IP2 could be a potential therapeutic target in atherosclerotic vascular diseases.

Cardiac-restricted Overexpression of TRAF3 Interacting Protein 2 (TRAF3IP2) Results in Spontaneous Development of Myocardial Hypertrophy, Fibrosis, and Dysfunction

“…In fact, in a recent study we have observed reduced atherosclerotic plaque burden in female Apoe/TRAF3IP2 double knock-out mice fed a Western diet (52). In another study, TRAF3IP2 was shown to mediate estrogen-deficient osteoporosis (53), further supporting the hypothesis that female sex hormones may negatively regulate TRAF3IP2 expression via mechanisms yet to be investigated.…”

Downregulation of Macrophage-Specific Act-1 Intensifies Periodontitis and Alveolar Bone Loss Possibly via TNF/NF-κB Signaling

“…Act1 had been reported to play a vital role in various inflammatory diseases (Pisitkun et al, 2010;Swaidani et al, 2011;Doyle et al, 2012;Wang et al, 2013;Sakamuri et al, 2016). Furthermore, our results indicated Act1 expression in macrophages infiltrated in gingiva and PAPT during periodontitis.…”

“…The macrophages are a key immune cell that regulates the pathophysiology of periodontitis ( Sima et al, 2019 ). Act1 is an intracellular signaling molecule that modulates inflammation in various diseases ( Pisitkun et al, 2010 ; Swaidani et al, 2011 ; Doyle et al, 2012 ; Sakamuri et al, 2016 ). However, the role of macrophage-specific Act1 on the pathophysiology of periodontitis has not been investigated yet.…”

RECK suppresses interleukin‐17/TRAF3IP2‐mediated MMP‐13 activation and human aortic smooth muscle cell migration and proliferation

“…Since TRAF3IP2 expression is regulated by multiple oxidative stress‐responsive nuclear transcription factors, including AP‐1, c/EBPβ, and IRF1 (Venkatesan et al, ; Zhao et al, ), it is highly likely that TRAF3IP2 expression is persistently upregulated in vascular inflammatory diseases. Of note, we have previously reported that TRAF3IP2 gene deletion significantly reduces atherosclerotic burden in ApoE –/– mice fed a high fat diet (Sakamuri et al, ).…”