PHARMACOLOGICAL MODULATION OF ANGIOTENSIN-II-INDUCED ARTERIAL MONONUCLEAR CELL ADHESION BY NUCLEAR RECEPTORS ACTIVATION


Maria J. Sanz, Ph.D., Institute of Health Research INCLIVA, Valencia, Spain

Objective: The need of effective strategies to treat and prevent atherosclerosis led us to investigate the effect of combined concentrations of Rosuvastatin (Rosu) and bexarotene (Bex) on angiotensin II (Ang-II)-induced arterial mononuclear cell (MC) recruitment.

Background: MC infiltration into the arterial subendothelium constitutes an early event of the atherogenic process. Rosu or Bex exert anti-inflammatory activity but concerns regarding the development of serious adverse effects have risen.

Methods: MC-endothelium interactions were evaluated in vitro using the dynamic flow chamber assay and human umbilical arterial endothelial cells (HUAEC). In vivo, arteriolar leukocyte adhesion was determined by intravital microscopy.

Results and conclusions: HUAEC were stimulated with Ang-II (1 µM) for 4h. Rosu (10-30 nM), Bex (0.3-1 µM) or different combinations of both, were added to plates 20h before Ang-II challenge. Surprisingly, a combination of Rosu (10 nM)+Bex (0.3 µM) which did not affect Ang-II-induced MC recruitment when either stimulus was assayed alone, significantly reduced this response. This effect was accompanied by diminished Ang-II-induced ICAM-1, VCAM-1 and CX3CL1 endothelial expression as well as CXCL1, CXCL8, CCL2 and CCL5 synthesis. Rosu+Bex HUAEC preincubation caused a drastic inhibition of RhoA activation by Ang-II and RhoA knockdown prevented Ang-II-induced arterial MC arrest. Increased RXRa, PPARa and PPAR? expression was detected in Bex+Rosu preincubated HUAEC and further stimulated with Ang-II. HUAEC transfection with RXRa, PPARa or PPAR? specific siRNA reversed the Bex+Rosu inhibitory response. In vivo, chronic administration of Ang-II to mice (500 ng/kg/min, 14 days) increased cremasteric arteriolar leukocyte adhesion. While chronic Rosu (1.25 mg/kg/day) or Bex (10 mg/kg/day) administration did not exert any significant effect on this parameter, their combined administration ameliorated it by 65%. These data indicate that combined administration of Rosu+Bex at suboptimal doses may constitute an alternative therapy in the control of the vascular inflammation minimizing the appearance of drug-associated adverse effects.