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      Anti–miR-148a regulates platelet FcγRIIA signaling and decreases thrombosis in vivo in mice

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          Abstract

          Publisher's Note: There is an [Related article:]Inside Blood Commentary on this article in this issue.

          Key Points

          • TULA-2 negatively regulates platelet FcγRIIA signaling by dephosphorylating Syk.

          • miR-148a targets TULA-2 and inhibition of miR-148a decreases FcγRIIA-mediated platelet activation and thrombosis in vivo.

          Abstract

          Fc receptor for IgG IIA (FcγRIIA)–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 FcγRIIA activation, the reasons for which remain unclear. We hypothesized that genetic variations between FcγRIIA hyper- and hyporesponders regulate FcγRIIA-mediated platelet reactivity and influence HIT susceptibility. Using unbiased genome-wide expression profiling, we observed that human hyporesponders to FcγRIIA 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 FcγRIIA 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 FcγRIIA transgenic mice upregulated the TULA-2 level and reduced FcγRIIA- and glycoprotein VI–mediated platelet α IIbβ 3 activation and calcium mobilization. Anti–miR-148a also reduced thrombus formation following intravascular platelet activation via FcγRIIA. These results show that TULA-2 is a target of miR-148a-3p, and TULA-2 serves as a negative regulator of FcγRIIA-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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          Author and article information

          Journal
          Blood
          Blood
          bloodjournal
          blood
          Blood
          Blood
          American Society of Hematology (Washington, DC )
          0006-4971
          1528-0020
          24 December 2015
          29 October 2015
          24 December 2016
          : 126
          : 26
          : 2871-2881
          Affiliations
          [1 ]Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, PA;
          [2 ]Baylor College of Medicine, Houston, TX; and
          [3 ]Sol Sherry Thrombosis Research Center, Temple University, Philadelphia, PA
          Author information
          http://orcid.org/0000-0001-7904-4978
          http://orcid.org/0000-0002-4182-1855
          http://orcid.org/0000-0002-8976-6410
          http://orcid.org/0000-0001-7267-5398
          Article
          PMC4692146 PMC4692146 4692146 2015/631135
          10.1182/blood-2015-02-631135
          4692146
          26516227
          7ec879f4-31c3-41bc-a35b-f721cf1ce7a8
          © 2015 by The American Society of Hematology
          History
          : 26 February 2015
          : 21 October 2015
          Page count
          Pages: 11
          Funding
          Funded by: National Institutes of Health
          Categories
          35
          37
          Thrombosis and Hemostasis

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