Circulation: Cardiovascular Genetics 2015-04-01

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

Index: Circ. Cardiovasc. Genet. 8(2) , 294-304, (2015)

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Abstract

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.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.These data demonstrate for the first time that SH2B3 is a crucial mediator of post-MI inflammation and fibrosis.© 2015 American Heart Association, Inc.

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