Forgione Marc A, Cap Andre, Liao Ronglih, Moldovan Nicanor I, Eberhardt Robert T, Lim Chee Chew, Jones John, Goldschmidt-Clermont Pascal J, Loscalzo Joseph
Evans Department of Medicine, Boston University School of Medicine, Boston, Mass, USA.
Circulation. 2002 Aug 27;106(9):1154-8. doi: 10.1161/01.cir.0000026820.87824.6a.
Oxidant stress has been implicated in the pathogenesis of atherothrombosis and other vascular disorders accompanied by endothelial dysfunction. Glutathione peroxidases (GPx) play an important role in the cellular defense against oxidant stress by utilizing glutathione (GSH) to reduce lipid hydroperoxides and hydrogen peroxide to their corresponding alcohols. Cellular GPx (GPx-1) is the principal intracellular isoform of GPx. We hypothesized that GPx-1 deficiency per se induces endothelial dysfunction and structural vascular abnormalities through increased oxidant stress.
A murine model of heterozygous deficiency of GPx-1 (GPx(+/-)) was investigated to examine this hypothesis. Mesenteric arterioles in GPx-1(+/-) mice demonstrated vasoconstriction to acetylcholine compared with vasodilation in wild-type mice (maximal change in vessel diameter, -13.0+/-2.8% versus 13.2+/-2.8%, P<0.0001). We also noted an increase in the plasma and aortic levels of the isoprostane iPF(2alpha)-III, a marker of oxidant stress, in GPx-1(+/-) mice compared with wild-type mice (170.4+/-23 pg/mL plasma versus 98.7+/-7.1 pg/mL plasma, P<0.03; 11.7+/-0.87 pg/mg aortic tissue versus 8.2+/-0.55 pg/mg aortic tissue, P<0.01). Histological sections from the coronary vasculature of GPx-1(+/-) mice show increased perivascular matrix deposition, an increase in the number of adventitial fibroblasts, and intimal thickening. These structural abnormalities in the myocardial vasculature were accompanied by diastolic dysfunction after ischemia-reperfusion.
These findings demonstrate that heterozygous deficiency of GPx-1 leads to endothelial dysfunction, possibly associated with increased oxidant stress, and to significant structural vascular and cardiac abnormalities. These data illustrate the importance of this key antioxidant enzyme in functional and structural responses of the mammalian cardiovascular system.
氧化应激与动脉粥样硬化血栓形成及其他伴有内皮功能障碍的血管疾病的发病机制有关。谷胱甘肽过氧化物酶（GPx）通过利用谷胱甘肽（GSH）将脂质氢过氧化物和过氧化氢还原为相应的醇类，在细胞抵御氧化应激中发挥重要作用。细胞GPx（GPx-1）是GPx的主要细胞内同工型。我们假设GPx-1缺乏本身会通过增加氧化应激诱导内皮功能障碍和血管结构异常。
研究了GPx-1杂合缺陷（GPx(+/-)）小鼠模型以检验该假设。与野生型小鼠的血管舒张相比，GPx-1(+/-)小鼠的肠系膜小动脉对乙酰胆碱表现出血管收缩（血管直径最大变化，-13.0±2.8%对13.2±2.8%，P<0.0001）。我们还注意到，与野生型小鼠相比，GPx-1(+/-)小鼠血浆和主动脉中氧化应激标志物异前列腺素iPF(2α)-III的水平升高（血浆170.4±23 pg/mL对98.7±7.1 pg/mL，P<0.03；主动脉组织11.7±0.87 pg/mg对8.2±0.55 pg/mg，P<0.01）。GPx-1(+/-)小鼠冠状血管的组织学切片显示血管周围基质沉积增加、外膜成纤维细胞数量增加和内膜增厚。心肌血管的这些结构异常伴随着缺血再灌注后的舒张功能障碍。
这些发现表明，GPx-1杂合缺陷导致内皮功能障碍，可能与氧化应激增加有关，并导致显著的血管结构和心脏异常。这些数据说明了这种关键抗氧化酶在哺乳动物心血管系统功能和结构反应中的重要性。
