期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：35
页码：15565-15570
DOI：10.1073/pnas.1002178107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：NAD(P)H oxidases (Noxs) produce O2- 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 O2- in the heart, indicating that Nox4 is a significant source of O2- 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 O2- 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.
