Hyperhomocystinemia impairs endothelial function and eNOS activity via PKC activation
Hyperhomocystinemia impairs endothelial function and eNOS activity via PKC activation
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DOI：
10.1161/01.atv.0000189559.87328.e4
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发表时间：
2005-12-01
影响因子：
8.7
通讯作者：
Wang, H
中科院分区：
文献类型：
--
作者：
Jiang, XH;Yang, F;Wang, H
高同型半胱氨酸血症（hyperhomocystinemia，HHcy）是心血管疾病的一个危险因素，与内皮功能障碍有关。在这项研究中，我们研究了高同型半胱氨酸在内皮功能障碍中的机制作用。方法和结果-通过使用2个功能模型，主动脉环和提睾肌的活体视频显微镜，我们发现动脉舒张反应于内皮依赖性血管舒张剂，乙酰胆碱或一氧化氮合酶（NOS）激活剂（A23187），在胱硫醚β-合酶缺失（CBS-/-）小鼠中显著受损。然而，在CBS-/-小鼠中，血管平滑肌细胞（VSMC）对一氧化氮（NO）供体（SNAP）的反应得以保留。此外，超氧化物歧化酶和过氧化氢酶未能恢复内皮依赖性血管舒张。CBS-/-小鼠的小鼠主动脉内皮细胞（MAECs）以及Hcy处理的小鼠和人主动脉内皮细胞（HAECs）中内皮型一氧化氮合酶（eNOS）活性显著降低。HCY介导的eNOS抑制-这是不获救的腺病毒转导的超氧化物歧化酶和谷胱甘肽过氧化物酶，或四氢生物蝶呤，sepiapterin，精氨酸在MAEC的reproductions-was与减少蛋白质表达和增加苏氨酸495磷酸化的eNOS在HAECs。最终，蛋白激酶C（PKC）抑制剂，GF 109203 X（GFX），逆转Hcy介导的eNOS失活和苏氨酸495磷酸化HAECs. Conclusions，这些数据表明，HHcy损害内皮功能和eNOS活性，主要是通过PKC激活。
Objective-A risk factor for cardiovascular disease, hyperhomocystinemia (HHcy), is associated with endothelial dysfunction. In this study, we examined the mechanistic role of HHcy in endothelial dysfunction.Methods and Results-Through the use of 2 functional models, aortic rings and intravital video microscopy of the cremaster, we found that arterial relaxation in response to the endothelium-dependent vessel relaxant, acetylcholine or the nitric oxide synthase ( NOS) activator (A23187), was significantly impaired in cystathionine beta-synthase null (CBS-/-) mice. However, the vascular smooth muscle cell (VSMC) response to the nitric oxide (NO) donor (SNAP) was preserved in CBS-/- mice. In addition, superoxide dismutase and catalase failed to restore endothelium-dependent vasodilatation. Endothelial nitric oxide synthase (eNOS) activity was significantly reduced in mouse aortic endothelial cells (MAECs) of CBS-/- mice, as well as in Hcy-treated mouse and human aortic endothelial cells (HAECs). Hcy-mediated eNOS inhibition-which was not rescued by adenoviral transduction of superoxide dismutase and glutathione peroxidase, or by tetrahydrobiopterin, sepiapterin, and arginine supplementations in MAEC-was associated with decreased protein expression and increased threonine 495 phosphorylation of eNOS in HAECs. Ultimately, a protein kinase C (PKC) inhibitor, GF109203X (GFX), reversed Hcy-mediated eNOS inactivation and threonine 495 phosphorylation in HAECs.Conclusions-These data suggest that HHcy impairs endothelial function and eNOS activity, primarily through PKC activation.