Combined sub-optimal doses of Rosuvastatin and Bexarotene impairs angiotensin II-induced arterial mononuclear cell adhesion through inhibition of Nox5 signaling pathways and increased RXR/PPARα and RXR/PPARγ interactions
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Combined sub-optimal doses of Rosuvastatin and Bexarotene impairs angiotensin II-induced arterial mononuclear cell adhesion through inhibition of Nox5 signaling pathways and increased RXR/PPARα and RXR/PPARγ interactions

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Combined sub-optimal doses of Rosuvastatin and Bexarotene impairs angiotensin II-induced arterial mononuclear cell adhesion through inhibition of Nox5 signaling pathways and increased RXR/PPARα and RXR/PPARγ interactions

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dc.contributor.author Escudero, Paula
dc.contributor.author Martinez de Marañón, Aranzazu
dc.contributor.author Collado, Aida
dc.contributor.author Gonzalez-Navarro, Herminia
dc.contributor.author Hermenegildo, Carlos
dc.contributor.author Peiró, Concepción
dc.contributor.author Piqueras, Laura
dc.contributor.author Sanz, Maria-Jesús
dc.date.accessioned 2020-09-30T17:38:43Z
dc.date.available 2020-09-30T17:38:43Z
dc.date.issued 2015
dc.identifier.uri https://hdl.handle.net/10550/75710
dc.description.abstract 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 μM), or a combination of both were administered to human umbilical arterial endothelial cells (HUAECs) 20 h before stimulation with 1 μM Ang-II (4 h). Surprisingly, a combination of Rosu (10 nM)+Bex (0.3 μM), 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 CX3CL1 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 RXRα, PPARα, and PPARγ expression in addition to RXRα/PPARα and RXRα/PPARγ 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.
dc.language.iso eng
dc.relation.ispartof Antioxidants & Redox Signaling, 2015, vol. 22, p. 901 -920
dc.rights.uri info:eu-repo/semantics/openAccess
dc.source Escudero, Paula Martinez de Marañón, Aranzazu Collado, Aida Gonzalez-Navarro, Herminia Hermenegildo, Carlos Peiró, Concepción Piqueras, Laura Sanz, Maria-Jesús 2015 Combined sub-optimal doses of Rosuvastatin and Bexarotene impairs angiotensin II-induced arterial mononuclear cell adhesion through inhibition of Nox5 signaling pathways and increased RXR/PPARα and RXR/PPARγ interactions Antioxidants & Redox Signaling 22 901 920
dc.subject Sistema cardiovascular
dc.subject Diabetis
dc.subject Artèries
dc.title Combined sub-optimal doses of Rosuvastatin and Bexarotene impairs angiotensin II-induced arterial mononuclear cell adhesion through inhibition of Nox5 signaling pathways and increased RXR/PPARα and RXR/PPARγ interactions
dc.type info:eu-repo/semantics/article
dc.date.updated 2020-09-30T17:38:43Z
dc.identifier.doi https://doi.org/10.1089/ars.2014.5969
dc.identifier.idgrec 108906

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