Combined Sub-Optimal Doses of Rosuvastatin and Bexarotene Impair Angiotensin II-Induced Arterial Mononuclear Cell Adhesion Through Inhibition of Nox5 Signaling Pathways and Increased RXR/PPARα and RXR/PPARγ Interactions

Aim: Mononuclear cell (MC) infiltration into the arterial subendothelium is a key event in atherogenesis. Rosuvastatin (Rosu) and bexarotene (Bex) exert anti-inflammatory activity, but serious dose-related adverse effects have emerged. The need for safer and effective strategies to prevent and treat atherosclerosis led us to test the effect of combined use of both drugs on angiotensin II (Ang-II)-induced arterial MC recruitment. Results: Vehicle, Rosu (10-30 nM), Bex (0.3-1 mu M), or a combination of both were administered to human umbilical arterial endothelial cells (HUAECs) 20 h before stimulation with 1 mu M Ang-II (4 h). Surprisingly, a combination of Rosu (10 nM)+Bex (0.3 mu M), which did not influence Ang-II-induced MC recruitment when either stimulus was studied alone, significantly reduced this response. This effect was accompanied by diminished Ang-II-induced ICAM-1, VCAM-1, and CX(3)CL1 endothelial expression and CXCL1, CXCL8, CCL2, and CCL5 production. Preincubation of HUAECs with Rosu+Bex inhibited Nox5 expression and Nox5-induced RhoA activation stimulated by Ang-II through increased RXR alpha, PPAR alpha, and PPAR gamma expression in addition to RXR alpha/PPAR alpha and RXR alpha/PPAR gamma interactions. In vivo, combined but not single administration of Rosu (1.25 mg/kg/day) and Bex (10 mg/kg/day) significantly diminished Ang-II-induced arteriolar leukocyte adhesion in the cremasteric microcirculation of C57BL/6 mice and atherosclerotic lesion formation in apoE(-/-) mice subjected to an atherogenic diet. Innovation and Conclusion: Combined administration of Bex+Rosu at suboptimal doses may constitute a new alternative and effective therapy in the control of the vascular inflammation associated to cardiometabolic disorders, since they synergize in their anti-inflammatory actions and may counteract their associated adverse effects. Antioxid. Redox Signal. 22, 901-920.