Hendgen-Cotta Ulrike B, Merx Marc W, Shiva Sruti, Schmitz Joel, Becher Stefanie, Klare Johann P, Steinhoff Heinz-Jürgen, Goedecke Axel, Schrader Jürgen, Gladwin Mark T, Kelm Malte, Rassaf Tienush
Department of Medicine, Division of Cardiology, Pulmonology and Vascular Medicine, University Hospital Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany.
Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10256-61. doi: 10.1073/pnas.0801336105. Epub 2008 Jul 16.
The nitrite anion is reduced to nitric oxide (NO*) as oxygen tension decreases. Whereas this pathway modulates hypoxic NO* signaling and mitochondrial respiration and limits myocardial infarction in mammalian species, the pathways to nitrite bioactivation remain uncertain. Studies suggest that hemoglobin and myoglobin may subserve a fundamental physiological function as hypoxia dependent nitrite reductases. Using myoglobin wild-type ((+/+)) and knockout ((-/-)) mice, we here test the central role of myoglobin as a functional nitrite reductase that regulates hypoxic NO* generation, controls cellular respiration, and therefore confirms a cytoprotective response to cardiac ischemia-reperfusion (I/R) injury. We find that myoglobin is responsible for nitrite-dependent NO* generation and cardiomyocyte protein iron-nitrosylation. Nitrite reduction to NO* by myoglobin dynamically inhibits cellular respiration and limits reactive oxygen species generation and mitochondrial enzyme oxidative inactivation after I/R injury. In isolated myoglobin(+/+) but not in myoglobin(-/-) hearts, nitrite treatment resulted in an improved recovery of postischemic left ventricular developed pressure of 29%. In vivo administration of nitrite reduced myocardial infarction by 61% in myoglobin(+/+) mice, whereas in myoglobin(-/-) mice nitrite had no protective effects. These data support an emerging paradigm that myoglobin and the heme globin family subserve a critical function as an intrinsic nitrite reductase that regulates responses to cellular hypoxia and reoxygenation [corrected]
随着氧张力降低，亚硝酸根阴离子被还原为一氧化氮（NO*）。尽管该途径可调节低氧NO信号传导和线粒体呼吸，并限制哺乳动物物种的心肌梗死，但亚硝酸生物活化的途径仍不确定。研究表明，血红蛋白和肌红蛋白可能作为依赖低氧的亚硝酸还原酶发挥基本的生理功能。我们使用肌红蛋白野生型（（+/+））和敲除型（（-/-））小鼠，在此测试肌红蛋白作为功能性亚硝酸还原酶的核心作用，该酶调节低氧NO的产生，控制细胞呼吸，从而证实对心脏缺血再灌注（I/R）损伤的细胞保护反应。我们发现肌红蛋白负责依赖亚硝酸盐的NO生成和心肌细胞蛋白铁亚硝基化。肌红蛋白将亚硝酸盐还原为NO可动态抑制细胞呼吸，并限制I/R损伤后活性氧的产生和线粒体酶的氧化失活。在分离的肌红蛋白（+/+）而非肌红蛋白（-/-）心脏中，亚硝酸盐处理使缺血后左心室舒张末压的恢复提高了29%。在体内给予亚硝酸盐可使肌红蛋白（+/+）小鼠的心肌梗死减少61%，而在肌红蛋白（-/-）小鼠中，亚硝酸盐没有保护作用。这些数据支持了一种新出现的范式，即肌红蛋白和血红素球蛋白家族作为一种内在的亚硝酸还原酶发挥关键功能，调节对细胞缺氧和复氧的反应[已修正]
