Critical Role of the NAD(P)H Oxidase Subunit p47phox for Left Ventricular Remodeling/Dysfunction and Survival After Myocardial Infarction

Medizinische Hochschule Hannover, Abteilung Kardiologie und Angiologie, Hannover, Germany.
Circulation Research (Impact Factor: 11.02). 03/2007; 100(6):894-903. DOI: 10.1161/01.RES.0000261657.76299.ff
Source: PubMed


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 (p47 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 O2μg·min; P<0.01) but not in p47 mice after MI (13.5±3.6 versus 15.5±3.5 nmol of O2μg·min), 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 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 mice, after MI. LV cavity dilatation and dysfunction 4 weeks after MI were markedly attenuated in p47 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 mice as compared with WT mice. Importantly, the survival rate was markedly higher in p47 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 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.

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Available from: Karsten Grote, Aug 27, 2014
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    • "The sources of ROS, particularly the superoxide radical (O 2 @BULLET− ), during heart I/R events are multiple, but the main sources identified so far include the mitochondrial electron transport system, and the activities of cytochrome p450, nitric oxide (NO) synthase, xanthine oxidase, lipoxygenases and cyclooxygenases as well as the NADPH oxidase complex [5]. Indeed, increased evidence implicates the NAPDH oxidase complex activity as a central mediator of I/R injury since mice lacking its cytosolic component p47 phox produced less superoxide, exhibited reduced cardiomyocyte hypertrophy, apoptosis, interstitial fibrosis and mortality upon myocardial ischemia [6]. Heart protection against redox imbalance include non-enzymatic antioxidants, such as reduced glutathione (GSH), thioredoxin, and alpha-tocopherol, that directly scavenge unpaired electrons of free radicals avoiding damage propagation [7], as well as antioxidant enzymes like superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and others [7] [8]. "
    Dataset: JSBMB 2013

    Full-text · Dataset · Jan 2016
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    • "The major findings of this study are that subclinical LPS exposure decreases cardiac expression of miR-29c and increases NOX2 after 3 days, with subsequent activation of fibrotic factors that lead to cardiac fibrosis after 2–4 weeks of recurrent exposure to LPS. Since decreased miR-29c [25] and increased NOX2 [20], [26]–[28] precede activation of other fibrotic factors and are associated with cardiac fibrosis in other conditions, this suggests a unique role of miR-29c and NOX2 in LPS-induced cardiac fibrosis. "
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    ABSTRACT: Background Exposure to subclinical levels of lipopolysaccharide (LPS) occurs commonly and is seemingly well tolerated. However, recurrent LPS exposure induces cardiac fibrosis over 2 to 3 months in a murine model, not mediated by the renin-angiotensin system. Subclinical LPS induces cardiac fibrosis by unique mechanisms. Methods In C57/Bl6 mice, LPS (10 mg/kg) or saline (control) were injected intraperitoneally once a week for 1–4 weeks. Mice showed no signs of distress, change in activity, appetite, or weight loss. Mice were euthanized after 3 days, 1, 2, or 4 weeks to measure cardiac expression of fibrosis-related genes and potential mediators (measured by QRT-PCR), including micro-RNA (miR) and NADPH oxidase (NOX). Collagen fraction area of the left ventricle was measured with picrosirius red staining. Cardiac fibroblasts isolated from adult mouse hearts were incubated with 0, 0.1, 1.0 or 10 ng/ml LPS for 48 hours. Results Cardiac miR expression profiling demonstrated decreased miR-29c after 3 and 7 days following LPS, which were confirmed by QRT-PCR. The earliest changes in fibrosis-related genes and mediators that occurred 3 days after LPS were increased cardiac expression of TIMP-1 and NOX-2 (but not of NOX-4). This persisted at 1 and 2 weeks, with additional increases in collagen Iα1, collagen IIIα1, MMP2, MMP9, TIMP1, TIMP2, and periostin. There was no change in TGF-β or connective tissue growth factor. Collagen fraction area of the left ventricle increased after 2 and 4 weeks of LPS. LPS decreased miR-29c and increased NOX-2 in isolated cardiac fibroblasts. Conclusions Recurrent exposure to subclinical LPS induces cardiac fibrosis after 2–4 weeks. Early changes 3 days after LPS were decreased miR-29c and increased NOX2 and TIMP1, which persisted at 1 and 2 weeks, along with widespread activation of fibrosis-related genes. Decreased miR-29c and increased NOX2, which induce cardiac fibrosis in other conditions, may uniquely mediate LPS-induced cardiac fibrosis.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "Apoptosis was indexed by counting TUNEL positive cells per 100 nuclei in the infarcted tissue [15], [21]. ROS formation was measured and quantified by staining with DHE as previously described [25], [26]. "
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    ABSTRACT: Our previous study shows that treatment with apelin increases bone marrow cells (BMCs) recruitment and promotes cardiac repair after myocardial infarction (MI). The objective of this study was to investigate whether overexpression of apelin in BMCs improved cell therapy and accelerated cardiac repair and functional recovery in post-MI mice. Mouse myocardial infarction was achieved by coronary artery ligation and BMCs overexpressing apelin (apelin-BMCs) or GFP (GFP-BMCs) were injected into ischemic area immediately after surgery. In vitro, exposure of cultured BMCs to apelin led to a gradual increase in SDF-1á and CXCR4 expression. Intramyocardial delivery of apelin-BMCs in post-MI mice resulted in a significant increase number of APJ(+)/c-kit(+)/Sca1(+) cells in the injected area compared to GFP-BMCs treated post-MI mice. Treatment with apelin-BMCs increased expression of VEGF, Ang-1 and Tie-2 in post-MI mice. Apelin-BMCs treatment also significantly increased angiogenesis and attenuated cardiac fibrosis formation in post-MI mice. Most importantly, treatment with apelin-BMCs significantly improved left ventricular (LV) systolic function in post-MI mice. Mechanistically, Apelin-BMCs treatment led to a significant increase in Sirtuin3 (Sirt3) expression and reduction of reactive oxygen species (ROS) formation. Treatment of cultured BMCs with apelin also increased Notch3 expression and Akt phosphorylation. Apelin treatment further attenuated stress-induced apoptosis whereas knockout of Sirt3 abolished anti-apoptotic effect of apelin in cultured BMCs. Moreover, knockout of Sirt3 significantly attenuated apelin-BMCs-induced VEGF expression and angiogenesis in post-MI mice. Knockout of Sirt3 further blunted apelin-BMCs-mediated improvement of cardiac repair and systolic functional recovery in post-MI mice. These data suggest that apelin improves BMCs therapy on cardiac repair and systolic function in post-MI mice. Upregulation of Sirt3 may contribute to the protective effect of apelin-BMCs therapy.
    Full-text · Article · Sep 2013 · PLoS ONE
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