title: 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.
  
  
  RESULTS
  Because Adam17-knockout mice are not viable, we studied the effect of Adam17 deficiency on atherosclerosis in Adam17 hypomorphic mice (Adam17ex/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 Adam17ex/ex.Ldlr-/-mice developed ≈1.5-fold larger atherosclerotic lesions, which contained more macrophages and vascular smooth muscle cells than wild-type littermate controls (Adam17wt/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.
authors.affiliation: From the Institute of Laboratory Medicine (A.N., B.H.N., K.S., A.H., A.K., D.T., L.M.H.) and Institute for Cardiovascular Prevention (Z.Z., C.Weber, S.S.), Ludwig-Maximilians-University Munich, Germany; Institute of Biochemistry, Christian Albrechts University, Kiel, Germany (A.C., S.R.-J.); Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland (C.Wolfrum); and German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Germany (C. Weber, S.S.).
authors.forename: Alexandros
authors.initials: A
authors.lastname: Nicolaou
authors.affiliation: From the Institute of Laboratory Medicine (A.N., B.H.N., K.S., A.H., A.K., D.T., L.M.H.) and Institute for Cardiovascular Prevention (Z.Z., C.Weber, S.S.), Ludwig-Maximilians-University Munich, Germany; Institute of Biochemistry, Christian Albrechts University, Kiel, Germany (A.C., S.R.-J.); Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland (C.Wolfrum); and German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Germany (C. Weber, S.S.).
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: From the Institute of Laboratory Medicine (A.N., B.H.N., K.S., A.H., A.K., D.T., L.M.H.) and Institute for Cardiovascular Prevention (Z.Z., C.Weber, S.S.), Ludwig-Maximilians-University Munich, Germany; Institute of Biochemistry, Christian Albrechts University, Kiel, Germany (A.C., S.R.-J.); Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland (C.Wolfrum); and German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Germany (C. Weber, S.S.).
authors.forename: Bernd H
authors.initials: BH
authors.lastname: Northoff
authors.affiliation: From the Institute of Laboratory Medicine (A.N., B.H.N., K.S., A.H., A.K., D.T., L.M.H.) and Institute for Cardiovascular Prevention (Z.Z., C.Weber, S.S.), Ludwig-Maximilians-University Munich, Germany; Institute of Biochemistry, Christian Albrechts University, Kiel, Germany (A.C., S.R.-J.); Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland (C.Wolfrum); and German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Germany (C. Weber, S.S.).
authors.forename: Kristina
authors.initials: K
authors.lastname: Sass
authors.affiliation: From the Institute of Laboratory Medicine (A.N., B.H.N., K.S., A.H., A.K., D.T., L.M.H.) and Institute for Cardiovascular Prevention (Z.Z., C.Weber, S.S.), Ludwig-Maximilians-University Munich, Germany; Institute of Biochemistry, Christian Albrechts University, Kiel, Germany (A.C., S.R.-J.); Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland (C.Wolfrum); and German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Germany (C. Weber, S.S.).
authors.forename: Andreas
authors.initials: A
authors.lastname: Herbst
authors.affiliation: From the Institute of Laboratory Medicine (A.N., B.H.N., K.S., A.H., A.K., D.T., L.M.H.) and Institute for Cardiovascular Prevention (Z.Z., C.Weber, S.S.), Ludwig-Maximilians-University Munich, Germany; Institute of Biochemistry, Christian Albrechts University, Kiel, Germany (A.C., S.R.-J.); Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland (C.Wolfrum); and German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Germany (C. Weber, S.S.).
authors.forename: Alexander
authors.initials: A
authors.lastname: Kohlmaier
authors.affiliation: From the Institute of Laboratory Medicine (A.N., B.H.N., K.S., A.H., A.K., D.T., L.M.H.) and Institute for Cardiovascular Prevention (Z.Z., C.Weber, S.S.), Ludwig-Maximilians-University Munich, Germany; Institute of Biochemistry, Christian Albrechts University, Kiel, Germany (A.C., S.R.-J.); Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland (C.Wolfrum); and German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Germany (C. Weber, S.S.).
authors.forename: Athena
authors.initials: A
authors.lastname: Chalaris
authors.affiliation: From the Institute of Laboratory Medicine (A.N., B.H.N., K.S., A.H., A.K., D.T., L.M.H.) and Institute for Cardiovascular Prevention (Z.Z., C.Weber, S.S.), Ludwig-Maximilians-University Munich, Germany; Institute of Biochemistry, Christian Albrechts University, Kiel, Germany (A.C., S.R.-J.); Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland (C.Wolfrum); and German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Germany (C. Weber, S.S.).
authors.forename: Christian
authors.initials: C
authors.lastname: Wolfrum
authors.affiliation: From the Institute of Laboratory Medicine (A.N., B.H.N., K.S., A.H., A.K., D.T., L.M.H.) and Institute for Cardiovascular Prevention (Z.Z., C.Weber, S.S.), Ludwig-Maximilians-University Munich, Germany; Institute of Biochemistry, Christian Albrechts University, Kiel, Germany (A.C., S.R.-J.); Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland (C.Wolfrum); and German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Germany (C. Weber, S.S.).
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.affiliation: From the Institute of Laboratory Medicine (A.N., B.H.N., K.S., A.H., A.K., D.T., L.M.H.) and Institute for Cardiovascular Prevention (Z.Z., C.Weber, S.S.), Ludwig-Maximilians-University Munich, Germany; Institute of Biochemistry, Christian Albrechts University, Kiel, Germany (A.C., S.R.-J.); Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland (C.Wolfrum); and German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Germany (C. Weber, S.S.).
authors.forename: Sabine
authors.initials: S
authors.lastname: Steffens
authors.affiliation: From the Institute of Laboratory Medicine (A.N., B.H.N., K.S., A.H., A.K., D.T., L.M.H.) and Institute for Cardiovascular Prevention (Z.Z., C.Weber, S.S.), Ludwig-Maximilians-University Munich, Germany; Institute of Biochemistry, Christian Albrechts University, Kiel, Germany (A.C., S.R.-J.); Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland (C.Wolfrum); and German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Germany (C. Weber, S.S.).
authors.forename: Stefan
authors.initials: S
authors.lastname: Rose-John
authors.affiliation: From the Institute of Laboratory Medicine (A.N., B.H.N., K.S., A.H., A.K., D.T., L.M.H.) and Institute for Cardiovascular Prevention (Z.Z., C.Weber, S.S.), Ludwig-Maximilians-University Munich, Germany; Institute of Biochemistry, Christian Albrechts University, Kiel, Germany (A.C., S.R.-J.); Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland (C.Wolfrum); and German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Germany (C. Weber, S.S.).
authors.forename: Daniel
authors.initials: D
authors.lastname: Teupser
authors.affiliation: From the Institute of Laboratory Medicine (A.N., B.H.N., K.S., A.H., A.K., D.T., L.M.H.) and Institute for Cardiovascular Prevention (Z.Z., C.Weber, S.S.), Ludwig-Maximilians-University Munich, Germany; Institute of Biochemistry, Christian Albrechts University, Kiel, Germany (A.C., S.R.-J.); Institute of Food, Nutrition and Health, ETH Zurich, Schwerzenbach, Switzerland (C.Wolfrum); and German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Germany (C. Weber, S.S.). lesca.holdt@med.uni-muenchen.de.
authors.forename: Lesca M
authors.initials: LM
authors.lastname: Holdt
mesh_terms: D000072198:ADAM17 Protein / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D001011:Aorta / Q000201:enzymology* / Q000473:pathology; D001018:Aortic Diseases / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D017209:Apoptosis; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002448:Cell Adhesion; D049109:Cell Proliferation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000201:enzymology / Q000473:pathology; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000201:enzymology / Q000473:pathology; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D034622:RNA Interference; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D011973:Receptors, LDL; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse
keywords: atherosclerosis; metalloproteases; models, genetic; receptors, tumor necrosis factor; vascular disease