Journal
BLOOD
Volume 126, Issue 26, Pages 2871-2881Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2015-02-631135
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Funding
- National Institutes of Health, National Heart, Lung and Blood Institute [R01 HL102482, P01 HL110860, R01 HL106009]
- American Heart Association predoctoral fellowship [15PRE25690045]
- Cardeza Foundation
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Fc receptor for IgG IIA (Fc gamma RIIA)-mediated platelet activation is essential in heparin-induced thrombocytopenia (HIT) and other immune-mediated thrombocytopenia and thrombosis disorders. There is considerable interindividual variation in platelet FcgRIIA activation, the reasons for which remain unclear. We hypothesized that genetic variations between FcgRIIA hyper- and hyporesponders regulate Fc gamma RIIA-mediated platelet reactivity and influence HIT susceptibility. Using unbiased genome-wide expression profiling, we observed that human hyporesponders to FcgRIIA activation showed higher platelet T-cell ubiquitin ligand-2 (TULA-2) mRNA expression than hyperresponders. Silent interfering RNA-mediated knockdown of TULA-2 resulted in hyperphosphorylation of spleen tyrosine kinase following FcgRIIA activation in HEL cells. Significantly, we found miR-148a-3p targeted and inhibited both human and mouse TULA-2 mRNA. Inhibition of miR-148a in Fc gamma RIIA transgenic mice upregulated the TULA-2 level and reduced Fc gamma RIIA- and glycoprotein VI-mediated platelet alpha(IIb)beta(3) activation and calcium mobilization. Anti-miR-148a also reduced thrombus formation following intravascular platelet activation via Fc gamma RIIA. These results show that TULA-2 is a target of miR-148a-3p, and TULA-2 serves as a negative regulator of Fc gamma RIIA-mediated platelet activation. This is also the first study to show the effects of in vivo miRNA inhibition on platelet reactivity. Our work suggests that modulating miR-148a expression is a potential therapeutic approach for thrombosis.
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