In the present study, we tested the hypothesis that the PPARγ (peroxisome-proliferator-activated receptor γ) activator rosiglitazone improves vascular structure and function in aged hyperhomocysteinaemic MTHFR (methylene tetrahydrofolate reductase) gene heterozygous knockout (mthfr+/−) mice fed a HCD (high-cholesterol diet), a model of high cardiovascular risk. One-year-old mthfr+/− mice were fed or not HCD (6 mg·kg−1 of body weight·day−1) and treated or not with rosiglitazone (20 mg·kg−1 of body weight·day−1) for 90 days and compared with wild-type mice. Endothelium-dependent relaxation of carotid arteries was significantly impaired (−40%) only in rosiglitazone-treated HCD-fed mthfr+/− mice. Carotid M/L (media-to-lumen ratio) and CSA (cross-sectional area) were increased (2-fold) in mthfr+/− mice fed or not HCD compared with wild-type mice (P<0.05). Rosiglitazone reduced M/L and CSA only in mthfr+/− mice fed a normal diet. Superoxide production was increased in mthfr+/− mice fed HCD treated or not with rosiglitazone, whereas plasma nitrite was decreased by rosiglitazone in mice fed or not HCD. PRMT-1 (protein arginine methyltransferase-1), involved in synthesis of the NO (nitric oxide) synthase inhibitor ADMA (asymmetric ω-NG,NG-dimethylarginine), and ADMA were increased only in rosiglitazone-treated HCD-fed mthfr+/− mice. Rosiglitazone had both beneficial and deleterious vascular effects in this animal model of high cardiovascular risk: it prevented carotid remodelling, but impaired endothelial function in part through enhanced oxidative stress and increased ADMA production in mice at high cardiovascular risk.
Countervailing vascular effects of rosiglitazone in high cardiovascular risk mice: role of oxidative stress and PRMT-1
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Carmine Savoia, Talin Ebrahimian, Catherine A. Lemarié, Pierre Paradis, Marc Iglarz, Farhad Amiri, Danesh Javeshgani, Ernesto L. Schiffrin; Countervailing vascular effects of rosiglitazone in high cardiovascular risk mice: role of oxidative stress and PRMT-1. Clin Sci (Lond) 1 May 2010; 118 (9): 583–592. doi: https://doi.org/10.1042/CS20090289
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