Michael J Flister1, Matthew J Hoffman1, Angela Lemke1, Sasha Z Prisco1, Nathan Rudemiller1, Caitlin C O'Meara1, Shirng-Wern Tsaih1, Carol Moreno1, Aron M Geurts1, Jozef Lazar1, Neeta Adhikari1, Jennifer L Hall1, Howard J Jacob2. 1. 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.). 2. 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.
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. 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.
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 failurepatients 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: Wei Wang; Yang Tang; Ying Wang; Liana Tascau; Joanna Balcerek; Wei Tong; Ross L Levine; Carrie Welch; Alan R Tall; Nan Wang Journal: Circ Res Date: 2016-07-18 Impact factor: 17.367
Authors: Tristan V de Jong; Hao Chen; Wesley A Brashear; Kelli J Kochan; Andrew E Hillhouse; Yaming Zhu; Isha S Dhande; Elizabeth A Hudson; Mary H Sumlut; Melissa L Smith; Theodore S Kalbfleisch; Peter A Doris Journal: Physiol Genomics Date: 2022-05-11 Impact factor: 4.297