Adam17 Deficiency Promotes Atherosclerosis by Enhanced TNFR2 Signaling in Mice

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— BecauseAdam17 -knockout mice are not viable, we studied the effect ofAdam17 deficiency on atherosclerosis inAdam17 hypomorphic mice (Adam17 ex/ex ), which have low residualAdam17 expression. To induce atherosclerosis, mice were crossed onto the low-density lipoprotein receptor (Ldlr )-deficient background. We found thatAdam17 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 −/− ). ReducedAdam17 -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 ofTnfr2 rescued from aberrant proliferation and from misregulation of apoptosis inAdam17 -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.