NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart
NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart
复制标题
DOI：
10.1073/pnas.1002178107
复制
发表时间：
2010-08-31
影响因子：
11.1
通讯作者：
Sadoshima, Junichi
中科院分区：
文献类型：
--
作者：
Kuroda, Junya;Ago, Tetsuro;Sadoshima, Junichi
NAD(P)H氧化酶(NOxs)产生O(2)(-)，在心血管病理生理中起重要作用。NOX4亚型主要在心肌细胞的线粒体中表达。为了阐明内源性NOX4在心脏中的作用，我们培育了心脏特异的NOX4(-/-)(c-NOX4(-/-))小鼠。在c-NOX4(-/-)小鼠中，NOX4的表达以心脏特异的方式受到抑制，而在其他NOx酶中没有代偿性上调。这些小鼠心脏中的O(2)(-)水平降低，表明NOX4是心肌细胞中O(2)(-)的重要来源。年轻c-NOX4(-/-)小鼠的基础心脏表型正常。而c-NOX4(-/-)组小鼠心肌肥厚、间质纤维化和细胞凋亡明显减轻，心肌细胞凋亡明显减轻，心功能明显改善。C-NOX4(-/-)小鼠的线粒体肿胀、细胞色素c的释放、线粒体DNA和乌头酸酶活性的降低均被减弱。另一方面，NOX4在小鼠心脏中的过表达加剧了PO引起的心功能障碍、纤维化和细胞凋亡。这些结果表明，心肌细胞中的NOX4是线粒体氧化应激的主要来源，从而介导了PO期间的线粒体和心脏功能障碍。
NAD(P)H oxidases (Noxs) produce O(2)(-) and play an important role in cardiovascular pathophysiology. The Nox4 isoform is expressed primarily in the mitochondria in cardiac myocytes. To elucidate the function of endogenous Nox4 in the heart, we generated cardiac-specific Nox4(-/-) (c-Nox4(-/-)) mice. Nox4 expression was inhibited in c-Nox4(-/-) mice in a heart-specific manner, and there was no compensatory up-regulation in other Nox enzymes. These mice exhibited reduced levels of O(2)(-) in the heart, indicating that Nox4 is a significant source of O(2)(-) in cardiac myocytes. The baseline cardiac phenotype was normal in young c-Nox4(-/-) mice. In response to pressure overload(PO), however, increases in Nox4 expression and O(2)(-) production in mitochondria were abolished in c-Nox4(-/-) mice, and c-Nox4(-/-) mice exhibited significantly attenuated cardiac hypertrophy, interstitial fibrosis and apoptosis, and better cardiac function compared with WT mice. Mitochondrial swelling, cytochrome c release, and decreases in both mitochondrial DNA and aconitase activity in response to PO were attenuated in c-Nox4(-/-) mice. On the other hand, overexpression of Nox4 in mouse hearts exacerbated cardiac dysfunction, fibrosis, and apoptosis in response to PO. These results suggest that Nox4 in cardiac myocytes is a major source of mitochondrial oxidative stress, thereby mediating mitochondrial and cardiac dysfunction during PO.