Synergistic vascular protective effects of combined low doses of PPARα and PPARγ activators in angiotensin II-induced hypertension in rats

Background and Purpose: Protective cardiovascular effects of peroxisome proliferator activated receptor (PPAR)α and PPARγ activators have been demonstrated. If used as vasoprotective agents in high risk vascular patients rather than for their metabolic benefits, these agents could be associated with unwanted side effects. As a proof of concept to support the use of combined low doses of PPARα and PPARγ as vascular protective agents in high risk vascular patients, we tested the hypothesis that combined low doses of PPARα (fenofibrate) and PPARγ (rosiglitazone) activators would provide vascular protective benefits similar to full individual doses of these PPAR agonists. Experimental Approach: Male Sprague-Dawley rats infused with Ang II (120 ng kg−1 min−1) were treated with rosiglitazone (1 or 2 mg kg−1 day−1) alone or concomitantly with fenofibrate (30 mg kg−1 day−1) for 7 days. Thereafter, vessels was assessed on a pressurized myograph, while NAD(P)H oxidase activity was determined by lucigenin chemiluminescence. Inflammation was evaluated using ELISA for NFκB and Western blotting for adhesion molecules. Key Results: Ang II-induced blood pressure increase, impaired acetylcholine-induced vasorelaxation, altered vascular structure, and enhanced vascular NAD(P)H oxidase activity and inflammation were significantly reduced by low dose rosiglitazone+fenofibrate. Conclusions and Implications: Combined low doses of PPARα and PPARγ activators attenuated development of hypertension, corrected vascular structural abnormalities, improved endothelial function, oxidative stress, and vascular inflammation. These agents used in low-dose combination have synergistic vascular protective effects. The clinical effects of combined low-dose PPARα and PPARγ activators as vascular protective therapy, potentially with reduced side-effects and drug interactions, should be assessed. British Journal of Pharmacology (2007) 151, 45–53. doi:10.1038/sj.bjp.0707215