Table 2.

A summary of NRs identified in platelets and their modes of action

Nuclear receptor	Ligands	Effect on platelet function	Mechanisms of action
GR27,28	Prednisolone	Negative regulation of platelet secondary mediator regulated effects (ADP and TXA2) In vitro Human platelets	Mechanism is unknown
ER25,26	Oestrogen—oestrone (E1), oestradiol (E2) and oestriol (E3)	Reduction in platelet responsiveness however, conflicting results exist In vitro, ex vivo, in vivo Human, mouse platelets	Mechanism is unknown
AR46–48	Testosterone Dihydrotestosterone	Potentiation of platelet aggregation In vitro and ex vivo Human and rat platelets	Mechanism is unknown
LXR31	GW3965 T0901317 24(S)-OH-cholesterol 27-OH-cholesterol	Inhibition of platelet function and thrombosis In vitro and in vivo Human and mouse platelets Conversion of platelets to the procoagulant state In vitro Human platelets	Reduced phosphorylation of early GPVI signalling components—Syk, LAT and PLCγ2 Increase LXR-Syk and LXR-PLCγ2 interaction Formation of coated platelets, including PS exposure, mitochondrial membrane depolarization (see Figure 1)
FXR29	GW4064 Chenodeoxycholic acid 6α-ethyl-chenodeoxycholic acid	Inhibition of platelet function, thrombosis and haemostasis In vitro and in vivo Human, mouse platelets	Cyclophillin D-dependent formation of coated platelets and closure of surface integrins Associated with PS exposure and mitochondrial membrane depolarization Augmented cGMP levels which promote PKG activity and phosphorylation of VASP S239 (see Figure 1)
		Conversion of platelets to the procoagulant state In vitro Human platelets
PPARα33	Fenofibrate Statins	Inhibition of platelet function In vitro Human, mouse platelets	Increase in cAMP levels PPARα–PKCα interaction and attenuation of PKCα (see Figure 2)
PPARβ/δ35	GW0742 L-165041	Inhibition of platelet function In vitro Human, mouse platelets	Increase in cAMP levels PPARα–PKCα interaction and attenuation of PKCα (see Figure 2)
PPARγ38,39	15d-PGJ2 Thiazolidinediones (rosiglitazone, ciglitazone, pioglitazone)	Inhibition of platelet function, thrombosis and haemostasis In vitro and in vivo Human, mouse platelets	Inhibition in phosphorylation of Syk and LAT to reduce GPVI signalling Reduced PPARγ–Syk and PPARγ–LAT interaction upon PPARγ ligand treatment Negative regulation of integrin αIIbβ3 outside-in via up-regulation of PKA activity and inhibition β3 phosphorylation (see Figure 2)
RAR41	atRA	Inhibition of cytoskeletal rearrangements and platelet spreading In vitro Human platelets	Disruption of RARα–Arp2/3 interactions. (see Figure 3)
RXR42,43	9-cis-retenoic acid Methoprene acid Docosahexaenoic acid	Inhibition of platelet function, thrombosis and haemostasis In vitro and in vivo Human, mouse platelets	RXR–Gq interaction and negative regulation of Rac activation to inhibit GPCR-mediated platelet activation Up-regulation of PKA activity and phosphorylation of VASP S157 in cAMP- and NFκβ-dependent manner (see Figure 3)
VDR45	Vitamin D and its metabolites	Low vitamin D plasma levels cause high mean platelet volume, a marker of platelet hyperactivity In vivo Human platelets	Mechanism is unknown