Countervailing vascular effects of rosiglitazone in high cardiovascular risk mice: role of oxidative stress and PRMT-1

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-N^G,N^G-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.