Critical Role of the NAD(P)H Oxidase Subunit p47 ^phox for Left Ventricular Remodeling/Dysfunction and Survival After Myocardial Infarction

Abstract

Accumulating evidence suggests a critical role of increased reactive oxygen species production for left ventricular (LV) remodeling and dysfunction after myocardial infarction (MI). An increased myocardial activity of the NAD(P)H oxidase, a major oxidant enzyme system, has been observed in human heart failure; however, the role of the NAD(P)H oxidase for LV remodeling and dysfunction after MI remains to be determined. MI was induced in wild-type (WT) mice (n=46) and mice lacking the cytosolic NAD(P)H oxidase component p47(phox) (p47(phox)-/- mice) (n=32). Infarct size was similar among the groups. NAD(P)H oxidase activity was markedly increased in remote LV myocardium of WT mice after MI as compared with sham-operated mice (83+/-8 versus 16.7+/-3.5 nmol of O(2)(-) x microg(-1) x min(-1); P<0.01) but not in p47(phox)-/- mice after MI (13.5+/-3.6 versus 15.5+/-3.5 nmol of O(2)(-) x microg(-1) x min(-1)), as assessed by electron-spin resonance spectroscopy using the spin probe CP-H. Furthermore, increased myocardial xanthine oxidase activity was observed in WT, but not in p47(phox)-/- mice after MI, suggesting NAD(P)H oxidase-dependent xanthine oxidase activation. Myocardial reactive oxygen species production was increased in WT mice, but not in p47(phox)-/- mice, after MI. LV cavity dilatation and dysfunction 4 weeks after MI were markedly attenuated in p47(phox)-/- mice as compared with WT mice, as assessed by echocardiography (LV end-diastolic diameter: 4.5+/-0.2 versus 6.3+/-0.3 mm, P<0.01; LV ejection fraction, 35.8+/-2.5 versus 22.6+/-4.4%, P<0.05). Furthermore, cardiomyocyte hypertrophy, apoptosis, and interstitial fibrosis were substantially reduced in p47(phox)-/- mice as compared with WT mice. Importantly, the survival rate was markedly higher in p47(phox)-/- mice as compared with WT mice after MI (72% versus 48%; P<0.05). These results suggest a pivotal role of NAD(P)H oxidase activation and its subunit p47(phox) for LV remodeling/dysfunction and survival after MI. The NAD(P)H oxidase system represents therefore a potential novel therapeutic target to prevent cardiac failure after MI.

Cardiac oxidative stress and remodeling following infarction: role of NADPH oxidase

“…In addition to gp91 phox , NADPH oxidase is composed of several other subunits including p22 phox , p40 phox , p47 phox , p67 phox and racl. Doerries et al have recently indicated that lack of p47 phox improved cardiac remodeling and ventricular function, indicating the importance of p47 phox in cardiac remodeling following MI (42). This observation suggests that the individual subunits of NADPH oxidase may differ in the effects they have on cardiac remodeling postMI.…”

NADPH oxidase-4 mediates protection against chronic load-induced stress in mouse hearts by enhancing angiogenesis

“…These differences in regulation, activation mechanism, subcellular location, and ROS generation translate into isoform-specific actions in isolated cellular models (9,19,22,33). In the heart, previous studies in mouse models of defective Nox2 activation or its deletion showed that Nox2 is detrimental during remodeling, causing increased hypertrophy, apoptosis, and contractile dysfunction (10)(11)(12)(13)(14)(15). The current results on Nox4, taken together with previous data on Nox2, indicate that the two isoforms contrast markedly in their effects on cardiac remodeling, with Nox2 being detrimental and Nox4 beneficial.…”

“…In nonphagocytic cells, however, Nox2 and other Nox proteins generate low levels of ROS that are involved in intracellular signaling (9). Previous studies using Nox2-null mice and other models showed that Nox2 in the heart is involved in the development of cardiac hypertrophy and contractile dysfunction induced by angiotensin II, pressure overload, or myocardial infarction (10)(11)(12)(13)(14)(15). Nox4 differs from Nox2 and other Nox enzymes in that it is regulated mainly by its expression level and does not require agonist stimulation or association with regulatory subunits for activation (16)(17)(18).…”

Homocysteine-induced cardiomyocyte apoptosis and plasma membrane flip-flop are independent of S-adenosylhomocysteine: a crucial role for nuclear p47phox

“…Theoretically, the lack of ROS production, notwithstanding increased nuclear NOX2 expression in ADAtreated cells, could be related to a lack of nuclear p47 phox expression, which is a crucial non-catalytic subunit, in induction of apoptosis, also in cardiomyocytes [25]. For this, we performed 3D confocal stackings to acquire optical sections of the cells to determine the exact intracellular location of p47 phox .…”