Adam17 Deficiency Promotes Atherosclerosis by Enhanced TNFR2 Signaling in Mice

Abstract

Objective— ADAM17 (a disintegrin and metalloproteinase 17) is a sheddase releasing different types of membrane-bound proteins, including adhesion molecules, cytokines, and their receptors as well as inflammatory mediators. Because these substrates modulate important mechanisms of atherosclerosis, we hypothesized that ADAM17 might be involved in the pathogenesis of this frequent disease. Approach and Results— Because Adam17 -knockout mice are not viable, we studied the effect of Adam17 deficiency on atherosclerosis in Adam17 hypomorphic mice ( Adam17 ex/ex ), which have low residual Adam17 expression. To induce atherosclerosis, mice were crossed onto the low-density lipoprotein receptor ( Ldlr )-deficient background. We found that Adam17 ex/ex .Ldlr −/− mice developed ≈1.5-fold larger atherosclerotic lesions, which contained more macrophages and vascular smooth muscle cells than wild-type littermate controls ( Adam17 wt/wt .Ldlr −/− ). Reduced Adam17 -mediated shedding led to significantly increased protein levels of membrane-resident TNFα (tumor necrosis factor) and TNFR2 (tumor necrosis factor receptor 2), resulting in a constitutive activation of TNFR2 signaling. At the same time, Adam17 deficiency promoted proatherosclerotic cellular functions, such as increased proliferation and reduced apoptosis in cultured macrophages and vascular smooth muscle cells and increased adhesion of macrophages to vascular endothelial cells. Because siRNA (small interfering RNA)-mediated knockdown of Tnfr2 rescued from aberrant proliferation and from misregulation of apoptosis in Adam17 -depleted cells, our data indicate that TNFR2 is an important effector of ADAM17 in our mouse model. Conclusions— Our results provide evidence for an atheroprotective role of ADAM17, which might be mediated by cleaving membrane-bound TNFα and TNFR2, thereby preventing overactivation of endogenous TNFR2 signaling in cells of the vasculature.

Cell Death in the Vessel Wall

“…Therefore, it was assumed that elevated levels of ADAM17 in the plaque would result in accumulation of apoptotic debris and expansion of atherosclerotic lesions. However, recently Nicolaou et al showed that in Ldlr−/− mice with a hypomorphic mutation that lowers ADAM17 expression, ADAM17-deficient cells had reduced apoptosis and atherosclerotic lesions from these mice had increased numbers of both macrophages and SMCs 17 . This was attributed to the increased signaling through TNF receptor 2 (TNFR2) and membrane-bound TNFα which promoted cell survival and pro-inflammatory signalling.…”

Ectodomain Shedding of RAGE and TLR4 as a Negative Feedback Regulation in High-Mobility Group Box 1-Activated Aortic Endothelial Cells

“…It could be a protective mechanism preventing overstimulation from the continuous or repeated exposure to HMGB1. In line with it, ADAM17 was atheroprotective and its deficiency was shown to promote atherosclerosis in mouse models of atherosclerosis [31,32].…”

Astragaloside III activates TACE/ADAM17‐dependent anti‐inflammatory and growth factor signaling in endothelial cells in a p38‐dependent fashion

“…Later they showed evidence that the atherosclerosis resistance of FVB.LDLR −/− mice could be explained by their increased TACE expression and activity (Holdt et al, ). The same group provided further evidence that TACE‐deficient LDLR −/− mice developed larger atherosclerotic lesions, which might be caused by the reduced shedding of TNF‐α and TNFR2 and resulted constitutive activation of TNFR2 signaling (Nicolaou et al, ). Therefore, TACE is likely a candidate gene of atherosclerosis susceptibility.…”

“…TACE is known to be responsible for the liberation of the inflammatory cytokine TNF‐α and its receptors, and also ligands of the epidermal growth factor receptor (EGFR), thus playing as an important switch in regulating cell proliferation, inflammation, and cancer progression (Scheller, Chalaris, Garbers, & Rose‐John, ). Holdt and his colleagues revealed in their works that the activity of TACE was closely related with the development of atherosclerosis (Holdt, Thiery, Breslow, & Teupser, ; Nicolaou et al, ). TACE was also proved to play an essential role in the post‐myocardial infarction repair by regulating angiogenesis (Fan et al, ).…”