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.
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Research Article|
February 09 2010
Countervailing vascular effects of rosiglitazone in high cardiovascular risk mice: role of oxidative stress and PRMT-1
Carmine Savoia;
Carmine Savoia
*Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada
†Cardiology Unit, Second Faculty of Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy
‡Research Center, Fatebenefratelli San Pietro Hospital, Rome, Italy
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Talin Ebrahimian;
Talin Ebrahimian
*Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada
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Catherine A. Lemarié;
Catherine A. Lemarié
*Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada
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Pierre Paradis;
Pierre Paradis
*Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada
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Marc Iglarz;
Marc Iglarz
*Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada
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Farhad Amiri;
Farhad Amiri
*Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada
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Danesh Javeshgani;
Danesh Javeshgani
*Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada
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Ernesto L. Schiffrin
*Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada
§Department of Medicine, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada
Correspondence: Professor Ernesto L. Schiffrin (email [email protected]).
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Publisher: Portland Press Ltd
Received:
May 27 2009
Revision Received:
November 25 2009
Accepted:
December 01 2009
Accepted Manuscript online:
December 01 2009
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2010 Biochemical Society
2010
Clin Sci (Lond) (2010) 118 (9): 583–592.
Article history
Received:
May 27 2009
Revision Received:
November 25 2009
Accepted:
December 01 2009
Accepted Manuscript online:
December 01 2009
Citation
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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