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 PPARgamma (peroxisome-proliferator-activated receptor gamma) 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 x kg-1 of body weight x day-1) and treated or not with rosiglitazone (20 mg x kg-1 of body weight x 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 omega-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.
Savoia
Carmine
C
Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada.
Ebrahimian
Talin
T
Lemarié
Catherine A
CA
Paradis
Pierre
P
Iglarz
Marc
M
Amiri
Farhad
F
Javeshgani
Danesh
D
Schiffrin
Ernesto L
EL
D000818:Animals; D002343:Carotid Artery, Internal / Q000503:physiopathology; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004730:Endothelium, Vascular / Q000503:physiopathology; D005260:Female; D020138:Hyperhomocysteinemia / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009573:Nitrites / Q000097:blood; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000502:physiology*; D000077154:Rosiglitazone; D013481:Superoxides / Q000378:metabolism; D045162:Thiazolidinediones / Q000009:adverse effects / Q000627:therapeutic use*
D002791:Cholesterol, Dietary; D009573:Nitrites; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D013481:Superoxides; D002784:Cholesterol; D042965:Methylenetetrahydrofolate Reductase (NADPH2); C546338:Prmt1 protein, mouse; D011484:Protein-Arginine N-Methyltransferases