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SH2B3 Is a Genetic Determinant of Cardiac Inflammation and Fibrosis.
Flister, Michael J; Hoffman, Matthew J; Lemke, Angela; Prisco, Sasha Z; Rudemiller, Nathan; O'Meara, Caitlin C; Tsaih, Shirng-Wern; Moreno, Carol; Geurts, Aron M; Lazar, Jozef; Adhikari, Neeta; Hall, Jennifer L; Jacob, Howard J.
Afiliação
  • Flister MJ; 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, Br
  • Hoffman MJ; 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, Br
  • Lemke A; 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, Br
  • Prisco SZ; 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, Br
  • Rudemiller N; 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, Br
  • O'Meara CC; 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, Br
  • Tsaih SW; 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, Br
  • Moreno C; 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, Br
  • Geurts AM; 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, Br
  • Lazar J; 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, Br
  • Adhikari N; 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, Br
  • Hall JL; 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, Br
  • Jacob HJ; 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, Br
Circ Cardiovasc Genet ; 8(2): 294-304, 2015 Apr.
Article em En | MEDLINE | ID: mdl-25628389
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. METHODS AND 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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas / Proteínas Musculares / Infarto do Miocárdio / Miocardite Idioma: En Ano de publicação: 2015 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas / Proteínas Musculares / Infarto do Miocárdio / Miocardite Idioma: En Ano de publicação: 2015 Tipo de documento: Article