Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada.
Clin Sci (Lond). 2010 Feb 9;118(9):583-92. doi: 10.1042/CS20090289.
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.
在本研究中，我们检验了一个假设，即过氧化物酶体增殖物激活受体γ（PPARγ）激动剂罗格列酮可改善老年高同型半胱氨酸血症 MTHFR（亚甲基四氢叶酸还原酶）基因杂合子敲除（mthfr+/-）小鼠的血管结构和功能，这些小鼠喂食高胆固醇饮食（HCD），这是一种高心血管风险模型。1 岁的 mthfr+/- 小鼠喂食或不喂食 HCD（6mgxkg-1体重x天-1），并接受或不接受罗格列酮（20mgxkg-1体重x天-1）治疗 90 天，并与野生型小鼠进行比较。仅在罗格列酮治疗的 HCD 喂养 mthfr+/- 小鼠中，颈动脉内皮依赖性松弛显著受损（-40%）。与野生型小鼠相比，mthfr+/- 小鼠无论是否喂食 HCD，颈动脉 M/L（中膜与管腔比）和 CSA（横截面积）均增加（2 倍）（P<0.05）。罗格列酮仅在喂食正常饮食的 mthfr+/- 小鼠中降低 M/L 和 CSA。HCD 喂养的 mthfr+/- 小鼠无论是否接受罗格列酮治疗，超氧化物产量均增加，而罗格列酮降低了 HCD 喂养或不喂养小鼠的血浆硝酸盐。PRMT-1（蛋白精氨酸甲基转移酶-1），参与合成一氧化氮（NO）合酶抑制剂 ADMA（不对称ω-NG，NG-二甲基精氨酸），以及 ADMA，仅在罗格列酮治疗的 HCD 喂养 mthfr+/- 小鼠中增加。在这种高心血管风险的动物模型中，罗格列酮既有有益的又有有害的血管作用：它可预防颈动脉重塑，但通过增强氧化应激和增加高心血管风险小鼠的 ADMA 产生，部分损害内皮功能。
