Ceramide changes the mediator of flow-induced vasodilation from nitric oxide to hydrogen peroxide in the human microcirculation.
Ceramide changes the mediator of flow-induced vasodilation from nitric oxide to hydrogen peroxide in the human microcirculation.
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DOI：
10.1161/circresaha.115.303881
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发表时间：
2014-08-15
影响因子：
20.1
通讯作者：
Gutterman DD
中科院分区：
文献类型：
--
作者：
Freed JK;Beyer AM;LoGiudice JA;Hockenberry JC;Gutterman DD
线粒体衍生的过氧化氢 (H2O2) 调节冠状动脉疾病 (CAD) 患者微血管中的血流诱导扩张 (FID)。神经酰胺（CAD 的独立危险因素和已知的线粒体活性氧 (ROS) 诱导剂）与 FID 之间的关系尚不清楚。我们检验了外源性神经酰胺诱导 FID 介质从一氧化氮 (NO) 转变为 H2O2 的假设。通过视频显微镜测量人体脂肪和心房组织阻力小动脉的内径变化。使用 MitoPeroxy Yellow 1 (Mito PY1) 测定小动脉中线粒体 H2O2 的产生。 PEG-过氧化氢酶、鱼藤酮和 Mito-TEMPO 会损害经神经酰胺预处理的健康脂肪小动脉中的 FID，而 Nω-硝基-L-精氨酸甲酯 (L-NAME) 则没有影响。线粒体 H2O2 的产生是响应于用神经酰胺预处理的健康脂肪血管中的流动而诱导的，并且在 PEG-过氧化氢酶的存在下被消除。免疫组织化学显示健康人和 CAD 患者的小动脉中都有神经酰胺积累。 L-NAME 减少了与 GW4869（一种中性鞘磷脂酶 (NSmase) 抑制剂）一起孵育的 CAD 患者的脂肪和心房血管的血管舒张，而 PEG-过氧化氢酶则没有效果。我们的数据表明，神经酰胺在 FID 介质从 NO 到线粒体衍生的 H2O2 的转变中发挥着不可或缺的作用，并且抑制神经酰胺的产生可以将扩张机制恢复为 NO。神经酰胺可能是预防和治疗与动脉粥样硬化相关的血管功能障碍的重要靶点。
Mitochondrial-derived hydrogen peroxide (H2O2) regulates flow-induced dilation (FID) in microvessels from patients with coronary artery disease (CAD). The relationship between ceramide, an independent risk factor for CAD and a known inducer of mitochondrial reactive oxygen species (ROS), and FID is unknown. We examined the hypothesis that exogenous ceramide induces a switch in the mediator of FID from nitric oxide (NO) to H2O2. Internal diameter changes of resistance arterioles from human adipose and atrial tissue were measured by videomicroscopy. Mitochondrial H2O2 production was assayed in arterioles using MitoPeroxy Yellow 1 (Mito PY1). PEG-catalase, rotenone, and Mito-TEMPO, impaired FID in healthy adipose arterioles pre-treated with ceramide whereas Nω-Nitro-L-arginine methyl ester (L-NAME) had no effect. Mitochondrial H2O2 production was induced in response to flow in healthy adipose vessels pre-treated with ceramide and this was abolished in the presence of PEG-catalase. Immunohistochemistry demonstrated ceramide accumulation in arterioles from both healthy and CAD patients. L-NAME reduced vasodilation to flow in adipose as well as atrial vessels from patients with CAD incubated with GW4869, a neutral sphingomyelinase (NSmase) inhibitor, whereas PEG-catalase had no effect. Our data indicate that ceramide has an integral role in the transition of the mediator of FID from NO to mitochondrial-derived H2O2 and that inhibition of ceramide production can revert the mechanism of dilation back to NO. Ceramide may be an important target for preventing and treating vascular dysfunction associated with atherosclerosis.