AP-1–Dependent Transcriptional Regulation of NADPH Oxidase in Human Aortic Smooth Muscle Cells

Manea, Adrian; Manea, Simona-Adriana; Gafencu, Anca Violeta; Raicu, Monica; Simionescu, Maya

doi:10.1161/atvbaha.108.163592

Cited by 101 publications

(78 citation statements)

References 52 publications

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“…Next, we examined the expression of the target genes Cox-2 (Ptgs2), Nox-2, and p40 phox . [27][28][29] In keeping with our results, we found that Cox-2, Nox-2, and p40 phox were induced at 3 h after OGD, but induction was impaired in neurons after acute inhibition of TAK1 (Figures 4a-c). However, chronic inhibition of TAK1 did not interfere with the upregulation of Cox-2 and Nox-2, and only partially reduced the induction of p40 phox by OGD in neurons (Figures 4d-f).…”

Section: Resultssupporting

confidence: 88%

Acute inhibition of TAK1 protects against neuronal death in cerebral ischemia

et al. 2011

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Neuronal apoptosis contributes to ischemic brain damage and neurodegenerative disorders. Key regulators of neuronal apoptosis are the transcription factor NF-jB and the MAP kinases p38/MAPK and JNK, which share a common upstream activator, the mitogen-activated protein kinase kinase kinase (MAP3K) TGFb-activated kinase 1 (TAK1). Here we investigate the function of TAK1 in ischemia-induced neuronal apoptosis. In primary cortical neurons, TAK1 was activated by oxygen glucose deprivation (OGD), an in vitro model of cerebral ischemia. We found that short-term inhibition of TAK1 protected against OGD in vitro and reduced the infarct volume after middle cerebral artery occlusion in vivo. Prolonged inhibition or deletion of the TAK1 gene in neurons was, however, not protective. Short-term, but not prolonged inhibition of TAK1 interfered with the activation of p38/MAPK and JNK by OGD, the induction of the pro-oxidative genes Cox-2, Nox-2, and p40 phox , and the formation of superoxide. We found that prolonged TAK1 inhibition upregulated another MAP3K, apoptosis signal-regulating kinase-1, which is able to compensate for TAK1 inhibition. Our study demonstrates that TAK1 is a central target for short-term inhibition of key signaling pathways and neuroprotection in cerebral ischemia.

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Section: Resultssupporting

confidence: 88%

Acute inhibition of TAK1 protects against neuronal death in cerebral ischemia

et al. 2011

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“…The integral membrane protein p22 phox is an indispensable component of the superoxide-generating phagocyte NADPH oxidase, which is a central molecule in the production of superoxides. [45][46][47][48][49] Conversely, the expression of antioxidants SOD and TXN decreased significantly in infarcted myocardium of rats exposed to tobacco smoke compared to tobacco naïve.…”

Section: Discussionmentioning

confidence: 97%

Antioxidant N-acetyl cysteine reverses cigarette smoke-induced myocardial infarction by inhibiting inflammation and oxidative stress in a rat model

Khanna

Mehra

2012

Laboratory Investigation

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The contribution of chronic tobacco exposure in determining post-myocardial infarction (MI) left ventricular (LV) remodeling and possible therapeutic strategies has not been investigated systematically. In this small animal investigation, we demonstrate that chronic tobacco smoke exposure leading up to acute MI in rats is associated with greater histological extent of myocardial necrosis and consequent worse LV function. These findings are associated with increased transcriptomic expression of pro-inflammatory cytokines, tissue repair molecules and markers of oxidative stress in the myocardium. The results demonstrate that an N-acetyl cysteine (NAC) treatment significantly reduced tobacco-exposed induced infarct size and percent fractional shortening. A significantly increased LV end-systolic diameter was observed in tobacco-exposed sham compared to tobacco-naïve sham (4.92 ± 0.41 vs 3.45 ± 0.33; Po0.05), and tobacco-exposed MI compared to tobacco-naïve MI (8.24±0.3 vs 6.1±0.49; Po0.01) rats. Decreased intracardiac mRNA expression of the markers of inflammation, tissue repair and oxidative stress and circulating levels of pro-inflammatory cytokines accompanied these positive effects of NAC. The treatment of tobacco-exposed MI rats with NAC resulted in significantly increased levels of intracardiac mRNA expression of antioxidants, including superoxide dismutase, thioredoxin and nuclear factor-E2-related factor 2, as well as circulating levels of glutathione (7 ± 0.12 vs 10 ± 0.18; Pp0.001), where the levels were almost identical to the tobacco-naïve sham rats. These findings identify a novel post-infarction therapy for amelioration of the adverse effects of tobacco exposure on the infracted myocardium and advocate the use of dietary supplement antioxidants for habitual smokers to prevent and reverse cardiovascular adverse effects in the absence of successful achievement of cessation of smoking. Globally, tobacco smoke exposure remains a significant risk for the development of acute myocardial infarction (MI) irrespective of ethic or gender disparities. Exposure to tobacco smoke increases inflammation, oxidative stress 1-10 and decreases antioxidant expression. [11][12][13][14][15] Direct and indirect studies have demonstrated that oxidative stress from reactive oxygen species (ROS) generated through mitochondria, xanthine oxidase, and the NADPH oxidase system 16-21 is one of the important factors in the pathogenesis of myocardial ischemia. Decreased infarct size in superoxide dismutase (SOD)-producing transgenic mice suggests direct evidence for the role of involvement of ROS in MI. 22,23 In limited investigations, the use of antioxidants such as mercaptopropionyl glycine, edaravone and probucol have demonstrated varied effects on remodeling in animal models of MI, [24][25][26][27][28][29][30][31][32] with improvement in collagen content and histological changes. In this study, we sought to delineate the role of chronic tobacco smoke leading up to an acute MI by focusing on oxidative stress coupled with inflammat...

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“…Our findings of increased mRNA levels in PPHN PA and PASMC suggest that increased transcription and/or increased mRNA stability is involved. Other studies using systemic vascular SMC have shown that p22 phox transcription is activated by several ROSsensitive factors, including NF-jB (28) and AP-1 (27), while Nox4 transcription is upregulated by NFjB (28) and HIF-1a (9). Nox-derived H 2 O 2 is known to amplify its own production via a feed-forward mechanism in vascular disease (8), and exposure to exogenous H 2 O 2 increases superoxide generation via Nox in vascular SMC (25).…”

Section: Nox4 In Pphnmentioning

confidence: 99%

Increased p22^phox/Nox4 Expression Is Involved in Remodeling Through Hydrogen Peroxide Signaling in Experimental Persistent Pulmonary Hypertension of the Newborn

Wedgwood

Lakshminrusimha

Czech

et al. 2013

Antioxidants & Redox Signaling

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Aim: To determine if the NADPH oxidase isoform Nox4 contributes to increased H 2 O 2 generation in persistent pulmonary hypertension of the newborn (PPHN) pulmonary arteries (PA), and to identify downstream signaling targets of Nox4 that contribute to vascular remodeling and vasoconstriction. Results: PPHN was induced in lambs by antenatal ligation of the ductus arteriosus at 128 days gestation. After 9 days, lungs, PA, and PA smooth muscle cells (PASMC) were isolated from control and PPHN lambs. Increased expression of p22 phox and Nox4 in PPHN lungs, PA, and PASMC was associated with increased reactive oxygen species in PPHN PA, increased protein thiol oxidation in PPHN PASMC, and a decreased activity of extracellular superoxide dismutase (ecSOD) in the lungs and PASMC. Nox4 small interfering RNA (siRNA) decreased Nox4 expression and thiol oxidation and increased the ecSOD activity in PPHN PASMC. An increased activity of nuclear factor-kappa B (NFjB) and expression of its target gene cyclin D1 were detected in PPHN lungs, PA, and PASMC. Nox4 siRNA and catalase attenuated these increases in PASMC, and catalase decreased cyclin D1 expression in PPHN lungs. Innovation: This study demonstrates for the first time that Nox4 expression is elevated in a lamb model of neonatal pulmonary hypertension. It identifies increased NFjB and cyclin D1 expression and a decreased ecSOD activity as targets of increased Nox4 signaling. Conclusion: PPHN increases p22 phox and Nox4 expression and activity resulting in elevated H 2 O 2 levels in PPHN PA. Increased H 2 O 2 induces vasoconstriction via mechanisms involving ecSOD inactivation, and stimulates vascular remodeling via NFjB activation and increased cyclin D1 expression. Approaches that inhibit the pulmonary arterial Nox4 activity may attenuate vasoconstriction and vascular remodeling in PPHN.

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AP-1–Dependent Transcriptional Regulation of NADPH Oxidase in Human Aortic Smooth Muscle Cells

Cited by 101 publications

References 52 publications

Acute inhibition of TAK1 protects against neuronal death in cerebral ischemia

Acute inhibition of TAK1 protects against neuronal death in cerebral ischemia

Antioxidant N-acetyl cysteine reverses cigarette smoke-induced myocardial infarction by inhibiting inflammation and oxidative stress in a rat model

Increased p22^phox/Nox4 Expression Is Involved in Remodeling Through Hydrogen Peroxide Signaling in Experimental Persistent Pulmonary Hypertension of the Newborn

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AP-1–Dependent Transcriptional Regulation of NADPH Oxidase in Human Aortic Smooth Muscle Cells

Cited by 101 publications

References 52 publications

Acute inhibition of TAK1 protects against neuronal death in cerebral ischemia

Acute inhibition of TAK1 protects against neuronal death in cerebral ischemia

Antioxidant N-acetyl cysteine reverses cigarette smoke-induced myocardial infarction by inhibiting inflammation and oxidative stress in a rat model

Increased p22phox/Nox4 Expression Is Involved in Remodeling Through Hydrogen Peroxide Signaling in Experimental Persistent Pulmonary Hypertension of the Newborn

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Increased p22^phox/Nox4 Expression Is Involved in Remodeling Through Hydrogen Peroxide Signaling in Experimental Persistent Pulmonary Hypertension of the Newborn