RGD Reference Report - SH2B3 Is a Genetic Determinant of Cardiac Inflammation and Fibrosis. - Rat Genome Database

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SH2B3 Is a Genetic Determinant of Cardiac Inflammation and Fibrosis.

Authors: 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 
Citation: Flister MJ, etal., Circ Cardiovasc Genet. 2015 Apr;8(2):294-304. doi: 10.1161/CIRCGENETICS.114.000527. Epub 2015 Jan 27.
RGD ID: 12904914
Pubmed: PMID:25628389   (View Abstract at PubMed)
DOI: DOI:10.1161/CIRCGENETICS.114.000527   (Journal Full-text)


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 (-¿11%; 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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Sh2b3Ratnegative regulation of sprouting angiogenesis  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Sh2b3  (SH2B adaptor protein 3)
Sh2b3em2Mcwi  (SH2B adaptor protein 3; zinc finger nuclease induced mutant 2, Medical College of Wisconsin)

Genes (Mus musculus)
Sh2b3  (SH2B adaptor protein 3)

Genes (Homo sapiens)
SH2B3  (SH2B adaptor protein 3)

Strains
SS-Sh2b3em2Mcwi-/-  (SS-Sh2b3em2Mcwi-/Sh2b3em2Mcwi-)


Additional Information