[No authors listed]
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 (-Î11%; 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.
KEYWORDS: {{ getKeywords(articleDetailText.words) }}
Sample name | Organism | Experiment title | Sample type | Library instrument | Attributes | |||||||||||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
{{attr}} | ||||||||||||||||||||||||||||||||||||||||||||||||||||||
{{ dataList.sampleTitle }} | {{ dataList.organism }} | {{ dataList.expermentTitle }} | {{ dataList.sampleType }} | {{ dataList.libraryInstrument }} | {{ showAttributeName(index,attr,dataList.attributes) }} |
{{ list.authorName }} {{ list.authorName }} |