Hyperhomocysteinemia alters cardiac substrate metabolism by impairing nitric oxide bioavailability through oxidative stress
Hyperhomocysteinemia alters cardiac substrate metabolism by impairing nitric oxide bioavailability through oxidative stress
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DOI：
10.1161/circulationaha.106.652693
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发表时间：
2007-01-16
期刊：
影响因子：
37.8
通讯作者：
Hintze, Thomas H.
中科院分区：
文献类型：
--
作者：
Suematsu, Nobuhiro;Ojaimi, Caroline;Hintze, Thomas H.
背景-高同型半胱氨酸血症（HHcy）被认为是一种血管疾病，与氧化应激水平升高相关，导致NO清除。然而，HHcy对心功能尤其是心肌代谢的影响尚不清楚。方法与结果-清醒犬静脉注射L-同型半胱氨酸，并饲喂蛋氨酸使犬血浆同型半胱氨酸水平提高至急性10 μ mol/L，慢性24 μ mol/L。HHcy对血流动力学无显著影响。缬草碱诱导的no依赖性冠状动脉舒张（bezald - jarisch反射）减少32%，但通过同时静脉输注抗坏血酸或罗布麻碱恢复。急性和慢性HHcy显著增加了心脏对葡萄糖和乳酸的摄取，减少了对游离脂肪酸的摄取。HHcy显著降低缓激肽或碳水化合物诱导的体外心肌耗氧量降低，这种效果在与抗坏血酸、天冬氨酸或罗布麻素共孵育后完全恢复。Western blot分析显示Nox2增加（82%），内皮型一氧化氮合酶（39%）、磷酸化型内皮型一氧化氮合酶（39%）和超氧化物歧化酶-1（45%）减少。对慢性HHcy患者心脏组织基因表达的微阵列分析表明，心脏表型向代谢葡萄糖的酶转变。结论：HHcy通过生成超氧化物降低NO的生物利用度，直接调节心脏对底物的利用，而不依赖于血流动力学或心室功能的变化。与HHcy相关的心脏或冠心病的进展应根据心脏代谢和底物使用调节改变的影响进行评估。
Background - Hyperhomocysteinemia ( HHcy) has been considered a vascular disease associated with increased levels of oxidative stress that results in scavenging of NO. However, little is known of the impact of HHcy on cardiac function and especially myocardial metabolism.Methods and Results - L-Homocysteine was intravenously infused into conscious dogs, and the dogs were fed methionine to increase plasma homocysteine to 10 mu mol/L for acute and 24 mu mol/L for chronic HHcy. There was no significant change in hemodynamics with HHcy. Veratrine-induced, NO-dependent, coronary vasodilation ( Bezold-Jarisch reflex) was reduced by 32% but was restored by simultaneous intravenous infusion of ascorbic acid or apocynin. Acute and chronic HHcy significantly increased uptake of glucose and lactate and decreased uptake of free fatty acid by the heart. HHcy significantly decreased bradykinin- or carbachol- induced reduction of myocardial oxygen consumption in vitro, and this effect was completely restored by coincubation with ascorbic acid, Tempol, or apocynin. Western blot analysis indicated an increase in Nox2 ( 82%) and a reduction in endothelial nitric oxide synthase ( 39%), phospho-endothelial nitric oxide synthase ( 39%), and superoxide dismutase-1 ( 45%). Microarray analysis of gene expression in heart tissue from chronic HHcy indicated a switch in cardiac phenotype to enzymes that metabolize glucose.Conclusions - HHcy directly modulates substrate use by the heart independent of changes in hemodynamics or ventricular function by reducing NO bioavailability through the generation of superoxide. The progression of cardiac or coronary heart disease associated with HHcy should be evaluated in light of the impact of alterations in the regulation of cardiac metabolism and substrate use.