Role of RXRβ in platelet function and arterial thrombosis

Abstract

Objective: Retinoid X receptors (RXR) are a family of nuclear receptors that play critical roles in the regulation of numerous fundamental biological processes including cell proliferation, differentiation, and death. Earlier studies suggested that treatment with RXR agonists attenuates platelet activation in all adults (male and femal) and mice; however, the underlying molecular mechanisms have remained insufficiently understood. To elaborate further on this issue, we characterized megakaryocyte and platelet-specific RXR knockout mice to study platelet function in vitro and arterial thrombosis in vivo.Approach and results: First, we identified RXRβ as the dominant RXR receptor in mouse platelets, prompting us to generate a megakaryocyte and platelet-specific PF4 Cre ;RXRβ flox/flox mouse. Second, we studied activation, spreading, and aggregation of platelets from C57Bl/6 wild-type mice (WT), PF4 Cre+ ;RXRβ flox/flox mice, and PF4 Cre-;RXRβ flox/flox littermate controls in the presence or absence of RXR ligands, that is, 9-cis-retinoic acid (9cRA) and methoprene acid (MA). We found that in vitro treatment with RXR ligands attenuates spreading and aggregation of platelets and increases proplatelet particle formation from megakaryocytes (MK). However, these effects are also observed in RXRβ-deficient platelets and MKs and are thus independent of RXRβ. Third, we investigated arterial thrombus formation in an iron chloride (FeCl3)-induced vascular injury model in vivo, which is also not affected by the absence of RXRβ in platelets. Conclusions: Absence of the most abundant RXR receptor in mouse platelets, RXRβ, does not affect platelet function in vitro and thrombus formation in vivo. Furthermore, RXR agonists' mediated effects on platelet function are independent of RXRβ expression. Hence, our data do not support a significant contribution of RXRβ to arterial thrombosis in mice. K E Y W O R D S nuclear receptor, platelet function, retinoids, RXR, thrombosis S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Lüsebrink E, Warm V, Pircher J, et al. Role of RXRβ in platelet function and arterial thrombosis. J

MDM2-Mediated Ubiquitination of RXRβ Contributes to Mitochondrial Damage and Related Inflammation in Atherosclerosis

“…Recent advances reveal that RXRs may exert direct beneficial effects in cardiovascular diseases via homodimerization with itself or heterodimerization with other nuclear receptors [ 4 , 5 ]. Studies have shown that novel functions of RXRs in macrophage lipid homeostasis, inflammation activation, vascular protection and platelets contribute to the protective effect of RXRs in atherosclerosis [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 ]. However, most studies focused on RXRα.…”