Freed Julie K, Beyer Andreas M, LoGiudice John A, Hockenberry Joseph C, Gutterman David D
From the Departments of Anesthesiology (J.K.F), Medicine-Cardiovascular Center (A.M.B., J.C.H., D.D.G.), and Plastic Surgery (J.A.L.), Medical College of Wisconsin, Milwaukee; and VA Medical Center, Milwaukee, WI (D.D.G.).
Circ Res. 2014 Aug 15;115(5):525-32. doi: 10.1161/CIRCRESAHA.115.303881. Epub 2014 Jun 11.
Mitochondrial-derived hydrogen peroxide (H2O2) regulates flow-induced dilation (FID) in microvessels from patients with coronary artery disease. The relationship between ceramide, an independent risk factor for coronary artery disease and a known inducer of mitochondrial reactive oxygen species, and FID is unknown.
We examined the hypothesis that exogenous ceramide induces a switch in the mediator of FID from nitric oxide to H2O2.
Internal diameter changes of resistance arterioles from human adipose and atrial tissue were measured by video microscopy. Mitochondrial H2O2 production was assayed in arterioles using mito peroxy yellow 1. Polyethylene glycol-catalase, rotenone, and Mito-TEMPO impaired FID in healthy adipose arterioles pretreated with ceramide, whereas N(ω)-nitro-l-arginine methyl ester had no effect. Mitochondrial H2O2 production was induced in response to flow in healthy adipose vessels pretreated with ceramide, and this was abolished in the presence of polyethylene glycol-catalase. Immunohistochemistry demonstrated ceramide accumulation in arterioles from both healthy patients and patients with coronary artery disease. N(ω)-nitro-l-arginine methyl ester reduced vasodilation to flow in adipose as well as atrial vessels from patients with coronary artery disease incubated with GW4869, a neutral sphingomyelinase inhibitor, whereas polyethylene glycol-catalase had no effect.
Our data indicate that ceramide has an integral role in the transition of the mediator of FID from nitric oxide to mitochondrial-derived H2O2 and that inhibition of ceramide production can revert the mechanism of dilation back to nitric oxide. Ceramide may be an important target for preventing and treating vascular dysfunction associated with atherosclerosis.
线粒体衍生的过氧化氢（H2O2）调节冠状动脉疾病患者微血管中的血流诱导性扩张（FID）。神经酰胺是冠状动脉疾病的独立危险因素，也是线粒体活性氧的已知诱导剂，其与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介质从一氧化氮转变为H2O2这一假说。
通过视频显微镜测量人脂肪组织和心房组织中阻力小动脉的内径变化。使用线粒体过氧黄1在小动脉中检测线粒体H2O2的产生。聚乙二醇 - 过氧化氢酶、鱼藤酮和线粒体靶向抗氧化剂Mito-TEMPO损害了用神经酰胺预处理的健康脂肪小动脉中的FID，而N（ω）-硝基-L-精氨酸甲酯没有作用。在用神经酰胺预处理的健康脂肪血管中，血流可诱导线粒体H2O2产生，而在聚乙二醇 - 过氧化氢酶存在时这种诱导作用消失。免疫组织化学显示健康患者和冠状动脉疾病患者的小动脉中均有神经酰胺积累。N（ω）-硝基-L-精氨酸甲酯降低了用中性鞘磷脂酶抑制剂GW4869孵育的冠状动脉疾病患者脂肪组织和心房血管中血流引起的血管舒张，而聚乙二醇 - 过氧化氢酶没有作用。
我们的数据表明，神经酰胺在FID介质从一氧化氮向线粒体衍生的H2O2的转变中起重要作用，抑制神经酰胺产生可使血管舒张机制恢复为一氧化氮介导。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。
