Dumitrescu Cristian, Biondi Roberto, Xia Yong, Cardounel Arturo J, Druhan Lawrence J, Ambrosio Giuseppe, Zweier Jay L
Davis Heart and Lung Research Institute, Division of Cardiovascular Medicine, Department of Internal Medicine, College of Medicine, Ohio State University, Columbus, OH 43210, USA.
Proc Natl Acad Sci U S A. 2007 Sep 18;104(38):15081-6. doi: 10.1073/pnas.0702986104. Epub 2007 Sep 11.
Coronary vasodilation is impaired in the postischemic heart with a loss of endothelial nitric oxide synthase (eNOS) activity, but the mechanisms underlying ischemia-induced eNOS dysfunction are not understood. For nitric oxide (NO) synthesis, eNOS requires the redox-sensitive cofactor tetrahydrobiopterin (BH(4)); however, the role of BH(4) in ischemia-induced endothelial dysfunction remains unknown. Therefore, isolated rat hearts were subjected to varying durations of ischemia, and the alterations in NOS-dependent vasodilation were measured and correlated with assays of eNOS activity and cardiac BH(4) concentrations. Ischemia time-dependently decreased cardiac BH(4) content with 85, 95, or 97% irreversible degradation after 30, 45, or 60 min of ischemia, respectively. Paralleling the decreases in BH(4), reductions of eNOS activity were seen of 58, 86, or 92%, and NOS-derived superoxide production was greatly increased. Addition of 10 microM BH(4) enhanced eNOS activity in nonischemic hearts and partially restored activity after ischemia. It also suppressed NOS-derived superoxide production. Impaired coronary flow during postischemic reperfusion was improved by BH(4) infusion. Thus, BH(4) depletion contributes to postischemic eNOS dysfunction, and BH(4) treatment is effective in partial restoration of endothelium-dependent coronary flow. Supplementation of BH(4) may therefore be an important therapeutic approach to reverse endothelial dysfunction in postischemic tissues.
在缺血后心脏中，内皮型一氧化氮合酶（eNOS）活性丧失，冠状动脉舒张功能受损，但缺血诱导的eNOS功能障碍的潜在机制尚不清楚。对于一氧化氮（NO）的合成，eNOS需要对氧化还原敏感的辅因子四氢生物蝶呤（BH(4)）；然而，BH(4)在缺血诱导的内皮功能障碍中的作用仍然未知。因此，对离体大鼠心脏进行不同时长的缺血处理，测量一氧化氮合酶（NOS）依赖性血管舒张的变化，并将其与eNOS活性测定和心脏BH(4)浓度相关联。缺血时间依赖性地降低心脏BH(4)含量，缺血30、45或60分钟后分别有85%、95%或97%的不可逆降解。与BH(4)的降低平行，eNOS活性分别降低了58%、86%或92%，并且NOS衍生的超氧化物生成大大增加。添加10 microM BH(4)可增强非缺血心脏中的eNOS活性，并在缺血后部分恢复活性。它还抑制了NOS衍生的超氧化物生成。BH(4)输注改善了缺血后再灌注期间受损的冠状动脉血流。因此，BH(4)耗竭导致缺血后eNOS功能障碍，并且BH(4)治疗可有效部分恢复内皮依赖性冠状动脉血流。因此，补充BH(4)可能是逆转缺血后组织中内皮功能障碍的重要治疗方法。
