title: Hyperreactivity of junctional adhesion molecule A-deficient platelets accelerates atherosclerosis in hyperlipidemic mice.
abstract: BACKGROUND
  Besides their essential role in hemostasis, platelets also have functions in inflammation. In platelets, junctional adhesion molecule (JAM)-A was previously identified as an inhibitor of integrin αIIbβ3-mediated outside-in signaling and its genetic knockdown resulted in hyperreactivity.
  
  
  OBJECTIVE
  This gain-of-function was specifically exploited to investigate the role of platelet hyperreactivity in plaque development.
  
  
  RESULTS
  JAM-A-deficient platelets showed increased aggregation and cellular and sarcoma tyrosine-protein kinase activation. On αIIbβ3 ligation, JAM-A was shown to be dephosphorylated, which could be prevented by protein tyrosine phosphatase nonreceptor type 1 inhibition. Mice with or without platelet-specific (tr)JAM-A-deficiency in an apolipoprotein e (apoe(-/-)) background were fed a high-fat diet. After ≤12 weeks of diet, trJAM-A(-/-)apoe-/- mice showed increased aortic plaque formation when compared with trJAM-A(+/+) apoe(-/-) controls, and these differences were most evident at early time points. At 2 weeks, the plaques of the trJAM-A(-/-) apoe(-/-) animals revealed increased macrophage, T cell, and smooth muscle cell content. Interestingly, plasma levels of chemokines CC chemokine ligand 5 and CXC-chemokine ligand 4 were increased in the trJAM-A(-/-) apoe(-/-)mice, and JAM-A-deficient platelets showed increased binding to monocytes and neutrophils. Whole-blood perfusion experiments and intravital microscopy revealed increased recruitment of platelets and monocytes to the inflamed endothelium in blood of trJAM-A(-/-) apoe(-/-)mice. Notably, these proinflammatory effects of JAM-A-deficient platelets could be abolished by the inhibition of αIIbβ3 signaling in vitro.
  
  
  CONCLUSIONS
  Deletion of JAM-A causes a gain-of-function in platelets, with lower activation thresholds and increased inflammatory activities. This leads to an increase of plaque formation, particularly in early stages of the disease.
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK) (E.K., Z.Z., X.B., M.M.N.S., K.B., O.S., P.v.H., R.T.A.M., A.S., C.W., R.R.K.) and Division of Vascular and Endovascular Surgery (Z.Z., T.A.K.), Ludwig-Maximilians-University Munich, Munich, Germany; Department of Pathology, Academic Medical Center (AMC), Amsterdam, The Netherlands (O.S.); German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany (O.S., P.v.H., A.S., C.W.); and Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (N.J.M., J.M.E.M.C., R.T.A.M., T.M.H., C.W., R.R.K.).
authors.forename: Ela
authors.initials: E
authors.lastname: Karshovska
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK) (E.K., Z.Z., X.B., M.M.N.S., K.B., O.S., P.v.H., R.T.A.M., A.S., C.W., R.R.K.) and Division of Vascular and Endovascular Surgery (Z.Z., T.A.K.), Ludwig-Maximilians-University Munich, Munich, Germany; Department of Pathology, Academic Medical Center (AMC), Amsterdam, The Netherlands (O.S.); German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany (O.S., P.v.H., A.S., C.W.); and Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (N.J.M., J.M.E.M.C., R.T.A.M., T.M.H., C.W., R.R.K.).
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK) (E.K., Z.Z., X.B., M.M.N.S., K.B., O.S., P.v.H., R.T.A.M., A.S., C.W., R.R.K.) and Division of Vascular and Endovascular Surgery (Z.Z., T.A.K.), Ludwig-Maximilians-University Munich, Munich, Germany; Department of Pathology, Academic Medical Center (AMC), Amsterdam, The Netherlands (O.S.); German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany (O.S., P.v.H., A.S., C.W.); and Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (N.J.M., J.M.E.M.C., R.T.A.M., T.M.H., C.W., R.R.K.).
authors.forename: Xavier
authors.initials: X
authors.lastname: Blanchet
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK) (E.K., Z.Z., X.B., M.M.N.S., K.B., O.S., P.v.H., R.T.A.M., A.S., C.W., R.R.K.) and Division of Vascular and Endovascular Surgery (Z.Z., T.A.K.), Ludwig-Maximilians-University Munich, Munich, Germany; Department of Pathology, Academic Medical Center (AMC), Amsterdam, The Netherlands (O.S.); German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany (O.S., P.v.H., A.S., C.W.); and Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (N.J.M., J.M.E.M.C., R.T.A.M., T.M.H., C.W., R.R.K.).
authors.forename: Martin M N
authors.initials: MM
authors.lastname: Schmitt
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK) (E.K., Z.Z., X.B., M.M.N.S., K.B., O.S., P.v.H., R.T.A.M., A.S., C.W., R.R.K.) and Division of Vascular and Endovascular Surgery (Z.Z., T.A.K.), Ludwig-Maximilians-University Munich, Munich, Germany; Department of Pathology, Academic Medical Center (AMC), Amsterdam, The Netherlands (O.S.); German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany (O.S., P.v.H., A.S., C.W.); and Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (N.J.M., J.M.E.M.C., R.T.A.M., T.M.H., C.W., R.R.K.).
authors.forename: Kiril
authors.initials: K
authors.lastname: Bidzhekov
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK) (E.K., Z.Z., X.B., M.M.N.S., K.B., O.S., P.v.H., R.T.A.M., A.S., C.W., R.R.K.) and Division of Vascular and Endovascular Surgery (Z.Z., T.A.K.), Ludwig-Maximilians-University Munich, Munich, Germany; Department of Pathology, Academic Medical Center (AMC), Amsterdam, The Netherlands (O.S.); German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany (O.S., P.v.H., A.S., C.W.); and Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (N.J.M., J.M.E.M.C., R.T.A.M., T.M.H., C.W., R.R.K.).
authors.forename: Oliver
authors.initials: O
authors.lastname: Soehnlein
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK) (E.K., Z.Z., X.B., M.M.N.S., K.B., O.S., P.v.H., R.T.A.M., A.S., C.W., R.R.K.) and Division of Vascular and Endovascular Surgery (Z.Z., T.A.K.), Ludwig-Maximilians-University Munich, Munich, Germany; Department of Pathology, Academic Medical Center (AMC), Amsterdam, The Netherlands (O.S.); German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany (O.S., P.v.H., A.S., C.W.); and Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (N.J.M., J.M.E.M.C., R.T.A.M., T.M.H., C.W., R.R.K.).
authors.forename: Philipp
authors.initials: P
authors.lastname: von Hundelshausen
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK) (E.K., Z.Z., X.B., M.M.N.S., K.B., O.S., P.v.H., R.T.A.M., A.S., C.W., R.R.K.) and Division of Vascular and Endovascular Surgery (Z.Z., T.A.K.), Ludwig-Maximilians-University Munich, Munich, Germany; Department of Pathology, Academic Medical Center (AMC), Amsterdam, The Netherlands (O.S.); German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany (O.S., P.v.H., A.S., C.W.); and Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (N.J.M., J.M.E.M.C., R.T.A.M., T.M.H., C.W., R.R.K.).
authors.forename: Nadine J
authors.initials: NJ
authors.lastname: Mattheij
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK) (E.K., Z.Z., X.B., M.M.N.S., K.B., O.S., P.v.H., R.T.A.M., A.S., C.W., R.R.K.) and Division of Vascular and Endovascular Surgery (Z.Z., T.A.K.), Ludwig-Maximilians-University Munich, Munich, Germany; Department of Pathology, Academic Medical Center (AMC), Amsterdam, The Netherlands (O.S.); German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany (O.S., P.v.H., A.S., C.W.); and Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (N.J.M., J.M.E.M.C., R.T.A.M., T.M.H., C.W., R.R.K.).
authors.forename: Judith M E M
authors.initials: JM
authors.lastname: Cosemans
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK) (E.K., Z.Z., X.B., M.M.N.S., K.B., O.S., P.v.H., R.T.A.M., A.S., C.W., R.R.K.) and Division of Vascular and Endovascular Surgery (Z.Z., T.A.K.), Ludwig-Maximilians-University Munich, Munich, Germany; Department of Pathology, Academic Medical Center (AMC), Amsterdam, The Netherlands (O.S.); German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany (O.S., P.v.H., A.S., C.W.); and Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (N.J.M., J.M.E.M.C., R.T.A.M., T.M.H., C.W., R.R.K.).
authors.forename: Remco T A
authors.initials: RT
authors.lastname: Megens
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK) (E.K., Z.Z., X.B., M.M.N.S., K.B., O.S., P.v.H., R.T.A.M., A.S., C.W., R.R.K.) and Division of Vascular and Endovascular Surgery (Z.Z., T.A.K.), Ludwig-Maximilians-University Munich, Munich, Germany; Department of Pathology, Academic Medical Center (AMC), Amsterdam, The Netherlands (O.S.); German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany (O.S., P.v.H., A.S., C.W.); and Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (N.J.M., J.M.E.M.C., R.T.A.M., T.M.H., C.W., R.R.K.).
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Koeppel
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK) (E.K., Z.Z., X.B., M.M.N.S., K.B., O.S., P.v.H., R.T.A.M., A.S., C.W., R.R.K.) and Division of Vascular and Endovascular Surgery (Z.Z., T.A.K.), Ludwig-Maximilians-University Munich, Munich, Germany; Department of Pathology, Academic Medical Center (AMC), Amsterdam, The Netherlands (O.S.); German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany (O.S., P.v.H., A.S., C.W.); and Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (N.J.M., J.M.E.M.C., R.T.A.M., T.M.H., C.W., R.R.K.).
authors.forename: Andreas
authors.initials: A
authors.lastname: Schober
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK) (E.K., Z.Z., X.B., M.M.N.S., K.B., O.S., P.v.H., R.T.A.M., A.S., C.W., R.R.K.) and Division of Vascular and Endovascular Surgery (Z.Z., T.A.K.), Ludwig-Maximilians-University Munich, Munich, Germany; Department of Pathology, Academic Medical Center (AMC), Amsterdam, The Netherlands (O.S.); German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany (O.S., P.v.H., A.S., C.W.); and Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (N.J.M., J.M.E.M.C., R.T.A.M., T.M.H., C.W., R.R.K.).
authors.forename: Tilman M
authors.initials: TM
authors.lastname: Hackeng
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK) (E.K., Z.Z., X.B., M.M.N.S., K.B., O.S., P.v.H., R.T.A.M., A.S., C.W., R.R.K.) and Division of Vascular and Endovascular Surgery (Z.Z., T.A.K.), Ludwig-Maximilians-University Munich, Munich, Germany; Department of Pathology, Academic Medical Center (AMC), Amsterdam, The Netherlands (O.S.); German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany (O.S., P.v.H., A.S., C.W.); and Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (N.J.M., J.M.E.M.C., R.T.A.M., T.M.H., C.W., R.R.K.).
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.affiliation: From the Institute for Cardiovascular Prevention (IPEK) (E.K., Z.Z., X.B., M.M.N.S., K.B., O.S., P.v.H., R.T.A.M., A.S., C.W., R.R.K.) and Division of Vascular and Endovascular Surgery (Z.Z., T.A.K.), Ludwig-Maximilians-University Munich, Munich, Germany; Department of Pathology, Academic Medical Center (AMC), Amsterdam, The Netherlands (O.S.); German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany (O.S., P.v.H., A.S., C.W.); and Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, The Netherlands (N.J.M., J.M.E.M.C., R.T.A.M., T.M.H., C.W., R.R.K.). r.koenen@maastrichtuniversity.nl.
authors.forename: Rory R
authors.initials: RR
authors.lastname: Koenen
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism* / Q000473:pathology; D001018:Aortic Diseases / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D001792:Blood Platelets / Q000378:metabolism*; D002340:Carotid Artery Diseases / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood / Q000150:complications* / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D010974:Platelet Aggregation; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000097:blood / Q000172:deficiency* / Q000235:genetics; D013927:Thrombosis / Q000097:blood / Q000209:etiology; D013997:Time Factors; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D015815:Cell Adhesion Molecules; C498686:F11r protein, mouse; D018836:Inflammation Mediators; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011956:Receptors, Cell Surface; D019061:src-Family Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: atherosclerosis; blood platelets; cell adhesion molecules; inflammation; phosphoprotein phosphatases