期刊
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
卷 13, 期 11, 页码 2102-2107出版社
WILEY
DOI: 10.1111/jth.13129
关键词
gene knockout; Larg protein; mouse; mouse; platelets; RhoA protein; mouse; thrombosis
资金
- British Heart Foundation [RG/10/006/28299, PG/13/14/30023]
- Wellcome Trust [WT090093MA]
- British Heart Foundation [PG/13/14/30023, RG/10/006/28299] Funding Source: researchfish
Background: RhoA is an important regulator of platelet responses downstream of G(13), yet we still know little about its regulation in platelets. Leukemia-associated Rho guanine-nucleotide exchange factor (GEF [LARG]), a RhoA GEF, is highly expressed in platelets and may constitute a major upstream activator of RhoA. To this end, it is important to determine the role of LARG in platelet function and thrombosis. Methods and results: Using a platelet-specific gene knockout, we show that the absence of LARG results in a marked reduction in aggregation and dense-granule secretion in response to the thromboxane mimetic U46619 and proteinase-activated receptor 4-activating peptide, AYPGKF, but not to adenosine diphosphate. In a ferric chloride thrombosis model invivo, this translated into a defect, under mild injury conditions. Importantly, agonist-induced RhoA activation was not affected by the absence of LARG, although basal activity was reduced, suggesting that LARG may play a housekeeper role in regulating constitutive RhoA activity. Conclusions: LARG plays an important role in platelet function and thrombosis invivo. However, although LARG may have a role in regulating the resting activation state of RhoA, its role in regulating platelet function may principally be through RhoA-independent pathways, possibly through other Rho family members.
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