SH2B3 Is a Genetic Determinant of Cardiac Inflammation and Fibrosis

Michael J. Flister, Matthew J. Hoffman, Angela Lemke, Sasha Z Prisco, Nathan Rudemiller, Caitlin C. O'Meara, Shirng Wern Tsaih, Carol Moreno, Aron M. Geurts, Jozef Lazar, Neeta Adhikari, Jennifer L Hall, Howard J. Jacob

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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 (Sh2b3em2Mcwi), we assessed the role of Sh2b3 in post-MI fibrosis, leukocyte infiltration, angiogenesis, left ventricle contractility, and inflammatory gene expression. Compared with wild-type, Sh2b3em2Mcwi 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 Sh2b3em2Mcwi rats (1.7-fold; P<0.05), we observed no significant differences in left ventricle capillary density between wild-type and Sh2b3em2Mcwi rats. In total, 12 genes were significantly elevated in the post left anterior descending artery occluded/reperfused hearts of Sh2b3em2Mcwi 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.

Original languageEnglish (US)
Pages (from-to)294-304
Number of pages11
JournalCirculation: Cardiovascular Genetics
Volume8
Issue number2
DOIs
StatePublished - Apr 4 2015

Keywords

  • genetics
  • myocardial fibrosis
  • myocardial infarction
  • rats

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