title: SH2B3 Is a Genetic Determinant of Cardiac Inflammation and Fibrosis.
abstract: BACKGROUND
  Genome-wide association studies are powerful tools for nominating pathogenic variants, but offer little insight as to how candidate genes affect disease outcome. Such is the case for SH2B adaptor protein 3 (SH2B3), which is a negative regulator of multiple cytokine signaling pathways and is associated with increased risk of myocardial infarction (MI), but its role in post-MI inflammation and fibrosis is completely unknown.
  
  
  RESULTS
  Using an experimental model of MI (left anterior descending artery occlusion/reperfusion injury) in wild-type and Sh2b3 knockout rats (Sh2b3(em2Mcwi)), we assessed the role of Sh2b3 in post-MI fibrosis, leukocyte infiltration, angiogenesis, left ventricle contractility, and inflammatory gene expression. Compared with wild-type, Sh2b3(em2Mcwi) rats had significantly increased fibrosis (2.2-fold; P<0.05) and elevated leukocyte infiltration (>2-fold; P<0.05), which coincided with decreased left ventricle fractional shortening (-Δ11%; P<0.05) at 7 days post left anterior descending artery occlusion/reperfusion injury. Despite an increased angiogenic potential in Sh2b3(em2Mcwi) rats (1.7-fold; P<0.05), we observed no significant differences in left ventricle capillary density between wild-type and Sh2b3(em2Mcwi) rats. In total, 12 genes were significantly elevated in the post left anterior descending artery occluded/reperfused hearts of Sh2b3(em2Mcwi) rats relative to wild-type, of which 3 (NLRP12, CCR2, and IFNγ) were significantly elevated in the left ventricle of heart failure patients carrying the MI-associated rs3184504 [T] SH2B3 risk allele.
  
  
  CONCLUSIONS
  These data demonstrate for the first time that SH2B3 is a crucial mediator of post-MI inflammation and fibrosis.
authors: From the Human and Molecular Genetics Center (M.J.F., M.J.H., A.L., S.Z.P., S.-W.T., A.M.G., J.L., H.J.J.), Departments of Physiology (M.J.F., M.J.H., A.L., S.Z.P., N.R., A.M.G., H.J.J.), Dermatology (J.L.), and Pediatrics (H.J.J.), Medical College of Wisconsin, Milwaukee; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.C.O'M.); Department of Cardiovascular and Metabolic Disease at MedImmune, Cambridge, United Kingdom (C.M.); and Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis (N.A., J.L.H.).
authors: Michael J
authors: MJ
authors: Flister
authors: From the Human and Molecular Genetics Center (M.J.F., M.J.H., A.L., S.Z.P., S.-W.T., A.M.G., J.L., H.J.J.), Departments of Physiology (M.J.F., M.J.H., A.L., S.Z.P., N.R., A.M.G., H.J.J.), Dermatology (J.L.), and Pediatrics (H.J.J.), Medical College of Wisconsin, Milwaukee; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.C.O'M.); Department of Cardiovascular and Metabolic Disease at MedImmune, Cambridge, United Kingdom (C.M.); and Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis (N.A., J.L.H.).
authors: Matthew J
authors: MJ
authors: Hoffman
authors: From the Human and Molecular Genetics Center (M.J.F., M.J.H., A.L., S.Z.P., S.-W.T., A.M.G., J.L., H.J.J.), Departments of Physiology (M.J.F., M.J.H., A.L., S.Z.P., N.R., A.M.G., H.J.J.), Dermatology (J.L.), and Pediatrics (H.J.J.), Medical College of Wisconsin, Milwaukee; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.C.O'M.); Department of Cardiovascular and Metabolic Disease at MedImmune, Cambridge, United Kingdom (C.M.); and Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis (N.A., J.L.H.).
authors: Angela
authors: A
authors: Lemke
authors: From the Human and Molecular Genetics Center (M.J.F., M.J.H., A.L., S.Z.P., S.-W.T., A.M.G., J.L., H.J.J.), Departments of Physiology (M.J.F., M.J.H., A.L., S.Z.P., N.R., A.M.G., H.J.J.), Dermatology (J.L.), and Pediatrics (H.J.J.), Medical College of Wisconsin, Milwaukee; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.C.O'M.); Department of Cardiovascular and Metabolic Disease at MedImmune, Cambridge, United Kingdom (C.M.); and Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis (N.A., J.L.H.).
authors: Sasha Z
authors: SZ
authors: Prisco
authors: From the Human and Molecular Genetics Center (M.J.F., M.J.H., A.L., S.Z.P., S.-W.T., A.M.G., J.L., H.J.J.), Departments of Physiology (M.J.F., M.J.H., A.L., S.Z.P., N.R., A.M.G., H.J.J.), Dermatology (J.L.), and Pediatrics (H.J.J.), Medical College of Wisconsin, Milwaukee; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.C.O'M.); Department of Cardiovascular and Metabolic Disease at MedImmune, Cambridge, United Kingdom (C.M.); and Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis (N.A., J.L.H.).
authors: Nathan
authors: N
authors: Rudemiller
authors: From the Human and Molecular Genetics Center (M.J.F., M.J.H., A.L., S.Z.P., S.-W.T., A.M.G., J.L., H.J.J.), Departments of Physiology (M.J.F., M.J.H., A.L., S.Z.P., N.R., A.M.G., H.J.J.), Dermatology (J.L.), and Pediatrics (H.J.J.), Medical College of Wisconsin, Milwaukee; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.C.O'M.); Department of Cardiovascular and Metabolic Disease at MedImmune, Cambridge, United Kingdom (C.M.); and Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis (N.A., J.L.H.).
authors: Caitlin C
authors: CC
authors: O'Meara
authors: From the Human and Molecular Genetics Center (M.J.F., M.J.H., A.L., S.Z.P., S.-W.T., A.M.G., J.L., H.J.J.), Departments of Physiology (M.J.F., M.J.H., A.L., S.Z.P., N.R., A.M.G., H.J.J.), Dermatology (J.L.), and Pediatrics (H.J.J.), Medical College of Wisconsin, Milwaukee; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.C.O'M.); Department of Cardiovascular and Metabolic Disease at MedImmune, Cambridge, United Kingdom (C.M.); and Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis (N.A., J.L.H.).
authors: Shirng-Wern
authors: SW
authors: Tsaih
authors: From the Human and Molecular Genetics Center (M.J.F., M.J.H., A.L., S.Z.P., S.-W.T., A.M.G., J.L., H.J.J.), Departments of Physiology (M.J.F., M.J.H., A.L., S.Z.P., N.R., A.M.G., H.J.J.), Dermatology (J.L.), and Pediatrics (H.J.J.), Medical College of Wisconsin, Milwaukee; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.C.O'M.); Department of Cardiovascular and Metabolic Disease at MedImmune, Cambridge, United Kingdom (C.M.); and Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis (N.A., J.L.H.).
authors: Carol
authors: C
authors: Moreno
authors: From the Human and Molecular Genetics Center (M.J.F., M.J.H., A.L., S.Z.P., S.-W.T., A.M.G., J.L., H.J.J.), Departments of Physiology (M.J.F., M.J.H., A.L., S.Z.P., N.R., A.M.G., H.J.J.), Dermatology (J.L.), and Pediatrics (H.J.J.), Medical College of Wisconsin, Milwaukee; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.C.O'M.); Department of Cardiovascular and Metabolic Disease at MedImmune, Cambridge, United Kingdom (C.M.); and Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis (N.A., J.L.H.).
authors: Aron M
authors: AM
authors: Geurts
authors: From the Human and Molecular Genetics Center (M.J.F., M.J.H., A.L., S.Z.P., S.-W.T., A.M.G., J.L., H.J.J.), Departments of Physiology (M.J.F., M.J.H., A.L., S.Z.P., N.R., A.M.G., H.J.J.), Dermatology (J.L.), and Pediatrics (H.J.J.), Medical College of Wisconsin, Milwaukee; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.C.O'M.); Department of Cardiovascular and Metabolic Disease at MedImmune, Cambridge, United Kingdom (C.M.); and Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis (N.A., J.L.H.).
authors: Jozef
authors: J
authors: Lazar
authors: From the Human and Molecular Genetics Center (M.J.F., M.J.H., A.L., S.Z.P., S.-W.T., A.M.G., J.L., H.J.J.), Departments of Physiology (M.J.F., M.J.H., A.L., S.Z.P., N.R., A.M.G., H.J.J.), Dermatology (J.L.), and Pediatrics (H.J.J.), Medical College of Wisconsin, Milwaukee; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.C.O'M.); Department of Cardiovascular and Metabolic Disease at MedImmune, Cambridge, United Kingdom (C.M.); and Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis (N.A., J.L.H.).
authors: Neeta
authors: N
authors: Adhikari
authors: From the Human and Molecular Genetics Center (M.J.F., M.J.H., A.L., S.Z.P., S.-W.T., A.M.G., J.L., H.J.J.), Departments of Physiology (M.J.F., M.J.H., A.L., S.Z.P., N.R., A.M.G., H.J.J.), Dermatology (J.L.), and Pediatrics (H.J.J.), Medical College of Wisconsin, Milwaukee; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.C.O'M.); Department of Cardiovascular and Metabolic Disease at MedImmune, Cambridge, United Kingdom (C.M.); and Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis (N.A., J.L.H.).
authors: Jennifer L
authors: JL
authors: Hall
authors: From the Human and Molecular Genetics Center (M.J.F., M.J.H., A.L., S.Z.P., S.-W.T., A.M.G., J.L., H.J.J.), Departments of Physiology (M.J.F., M.J.H., A.L., S.Z.P., N.R., A.M.G., H.J.J.), Dermatology (J.L.), and Pediatrics (H.J.J.), Medical College of Wisconsin, Milwaukee; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (C.C.O'M.); Department of Cardiovascular and Metabolic Disease at MedImmune, Cambridge, United Kingdom (C.M.); and Lillehei Heart Institute, Department of Medicine, University of Minnesota, Minneapolis (N.A., J.L.H.). jacob@mcw.edu.
authors: Howard J
authors: HJ
authors: Jacob
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D004195:Disease Models, Animal; D005355:Fibrosis; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D009203:Myocardial Infarction / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009205:Myocarditis / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011922:Rats, Mutant Strains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D009124:Muscle Proteins; D011506:Proteins; C097176:Sh2b3 protein, rat
keywords: genetics; myocardial fibrosis; myocardial infarction; rats