NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart

Abstract

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.

Klotho Protects Against Indoxyl Sulphate-Induced Myocardial Hypertrophy

“…As reported, Nox2 and Nox4 are expressed in cardiomyocytes and myocardial fibroblasts, and their activation plays an important role in myocardial hypertrophy and/or cardiac remodeling. 29,30 In general, Nox-derived ROS production activates redox-sensitive signaling pathways and stimulates the transcription of hypertrophy-related genes, eventually resulting in cardiac hypertrophy. 31 In this study, a dose-dependent elevation of ROS production was detected in NRCMs after treatment with IS, and a remarkable increase in ROS level in the myocardial tissue was also observed in mice treated with IS (100 mg/kg per day) for 8 weeks (data not shown).…”

Nuclear Factor–Erythroid-2–Related Factor 2 in Aging and Lung Fibrosis

“…109 Since this report, several other studies have demonstrated a critical role of NOX4 in fibrosis involving the liver, 110 kidney, 111 and heart. 112 More recent studies demonstrate that the up-regulation of NOX4 is coupled to Nrf2 induction, and this adaptive response is critical to apoptosis susceptibility of myofibroblasts and resolution of fibrosis in young mice. 2 In contrast, in aged mice, there is impaired Nrf2 activation leading to an altered NOX4-Nrf2 redox balance and acquisition of an apoptosis-resistant myofibroblast phenotype resulting in persistent fibrosis.…”

The involvement of Nox4 in fine particulate matter exposure-induced cardiac injury in mice

“…Oxidative stress products such as superoxide radical (O 2 -) and hydroxyl radical (-OH) can attack the cell membrane and further lead to tissue oxidative injury (Mak et al, 2002). Nox4, as the important Nox isoform expressed in the heart, has been acknowledged as the principal source of oxidative stress, which can also mediate myocardial apoptosis (Kuroda et al, 2010).…”