Role of Mitogen-activated Protein Kinases in 4-Hydroxy-2-nonenal-induced Actin Remodeling and Barrier Function in Endothelial Cells

Usatyuk, Peter V.; Natarajan, Viswanathan

doi:10.1074/jbc.m311184200

Cited by 150 publications

(113 citation statements)

References 60 publications

(74 reference statements)

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“…12), confirming a major role for NADPH oxidase. Although signaling pathways whereby hyperoxia regulates endothelial NADPH oxidase have not been completely defined, involvement of MAPKs in NADPH oxidase activation and ROS production has been reported (10,44). Previous studies in human vascular and rat thoracic aortic VSMCs demonstrated that angiotensin II-dependent stimulation of NADPH oxidase is regulated in part by c-Src (18).…”

Section: Discussionmentioning

confidence: 99%

Src-mediated Tyrosine Phosphorylation of p47 in Hyperoxia-induced Activation of NADPH Oxidase and Generation of Reactive Oxygen Species in Lung Endothelial Cells

Chowdhury

Watkins

Parinandi

et al. 2005

Journal of Biological Chemistry

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136

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Oxygen therapy often rescues and reduces the mortality resulting from acute respiratory distress syndrome, chronic obstructive pulmonary diseases, exposure to toxic fumes, and drowning (1). However, prolonged exposure to supra-physiological concentrations of oxygen, referred to as hyperoxia, causes extensive damage to the alveolar-capillary barrier resulting in increased permeability and decreased lung function (2). Although the molecular mechanisms of hyperoxia-induced lung injury and cell death are complex, recent studies suggest that the generation of excessive reactive oxygen species (ROS), 1 loss of antioxidant defense pathways, cytokine-mediated inflammation, and modulation of signal transduction may regulate pulmonary edema and apoptosis/necrosis of endothelial and epithelial cells (3). The vascular endothelium has long been recognized to generate superoxide (O 2 . ), hydrogen peroxide (H 2 O 2 ), hydroxyl radical ( ⅐ OH), and nitric oxide (NO) via enzymatic and nonenzymatic reactions. In endothelial cells (ECs), in addition to the mitochondrial electron transport, other potential enzymatic pathways of ROS production include cyclooxygenase/lipoxygenase, cytochrome P450, xanthine oxidase, NADPH oxidase, NO synthase, and peroxidase. In the lung, the vascular NADPH oxidase seems to play an important role in excessive production of O 2 . in atherosclerosis, ischemic lung, pulmonary hypertension, and ventilator-associated lung injury (4 -9). NADPH oxidase catalyzes the one-electron reduction of molecular oxygen to O 2 . by using NADPH or NADH as an electron donor (9). Activated NADPH oxidase is a multimeric protein complex consisting of at least three cytosolic subunits of p47 phox , p67 phox , and p40 phox ; a regulatory small molecular weight G-protein of either Rac1 or Rac2 and a membraneassociated cytochrome b 558 reductase made up of p22 phox and gp91 phox . We and others (10, 11) have shown that most of the subcomponents of phagocytic NADPH oxidase are expressed in vascular ECs. ECs exhibit a low output in of O 2. production under basal conditions, and stimulation by TNF-␣, pulsatile stretch, hypoxia reoxygenation, and phorbol ester enhanced the

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Section: Discussionmentioning

confidence: 99%

Src-mediated Tyrosine Phosphorylation of p47 in Hyperoxia-induced Activation of NADPH Oxidase and Generation of Reactive Oxygen Species in Lung Endothelial Cells

Chowdhury

Watkins

Parinandi

et al. 2005

Journal of Biological Chemistry

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136

140

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“…This raises the possibility that the mechanism of HO-1 induction by HNE in pulmonary epithelial cells is different from other systems. As the lung is the "first line of defense," it is not surprising that pulmonary epithelial cells may have evolved mechanisms to rapidly respond to cellular insults.It is well established in the literature that HNE activates some, or even all, of the MAPK in other cell systems [38,[59][60][61][62]. We hypothesized that HNE-mediated activation of MAPK signaling pathways culminated in phosphorylation and/or nuclear translocation of transcription factors critical to the induction of HO-1 mRNA synthesis and was thus the mechanism for increased HO-1 protein and activity.…”

mentioning

confidence: 96%

HNE increases HO-1 through activation of the ERK pathway in pulmonary epithelial cells

Iles

Dickinson

Wigley

et al. 2005

Free Radical Biology and Medicine

101

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Heme oxygenase-1 (HO-1) is a key cytoprotective enzyme and an established marker of oxidative stress. Increased HO-1 expression has been found in the resident macrophages in the alveolar spaces of smokers. The lipid peroxidation product 4-hydroxynonenal (HNE) is also increased in the bronchial and alveolar epithelium in response to cigarette smoke. This suggests a link between a chronic environmental stress, HNE formation, and HO-1 induction. HNE is both an agent of oxidative stress in vivo and a potent cell signaling molecule. We hypothesize that HNE acts as an endogenously produced pulmonary signaling molecule that elicits an adaptive response culminating in the induction of HO-1. Here we demonstrate that HNE increases HO-1 mRNA, protein, and activity in pulmonary epithelial cells and identify ERK as a key pathway involved. Treatment with HNE increased ERK phosphorylation, c-Fos protein, JNK phosphorylation, c-Jun phosphorylation, and AP-1 binding. Whereas inhibiting the ERK pathway with the MEK inhibitor PD98059 significantly decreased HNEmediated ERK phosphorylation, c-Fos protein induction, AP-1 binding, and HO-1 protein induction, inhibition of the ERK pathway had no effect on HNE-induced HO-1 mRNA. This suggests that ERK is involved in the increase in HO-1 through regulation of translation rather than transcription. Keywords 4-Hydroxynonenal; Oxidative stress; HO-1; MAPK signaling; Free radicals Heme oxygenase-1 (HO-1) is an important cytoprotective enzyme and widely accepted marker of oxidative stress. HO-1 catalyzes the first and rate-limiting step in the catabolism of heme, which generates equimolar amounts of biliverdin, ferrous iron, and carbon monoxide [1][2][3]. Although heme is the major substrate of HO-1, a variety of non-heme-containing agents are also strong inducers of HO-1. HO-1 has been shown to respond to a number of proinflammatory cytokines, including TNF-α, . HO-1 is also induced by a variety of agents NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript that cause oxidative stress and/or in response to environmental stress [5][6][7][8]. For example, increased HO-1 expression has recently been found in the alveolar spaces in the resident macrophages of smokers [9]. Once induced, HO-1 provides protection against multiple types of tissue injury [10][11][12][13]; specific to the lung, overexpression of HO-1 in pulmonary epithelial cells has been shown to protect against oxygen toxicity [14]. In contrast, HO-1 deficiency in mice (HO-1 −/− ) increases susceptibility to inflammatory lung injury [15], as does HO-1 deficiency in humans [16]. Although the precise mechanisms by which HO-1 exerts its cytoprotective effects are not known, there is mounting evidence that carbon monoxide plays a key role in this process. For thorough reviews of the recent literature see [17,18].Another characteristic of oxidative stress is the formation of the lipid peroxidation product 4-hydroxy-2-nonenal (HNE). HNE has been shown to increase HO-1 in the cell [19,20], but the mechanism(s...

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“…Free radical-mediated lipid peroxidation and its reactive byproducts, like HNE are known to cause cellular structural perturbations and various redox-related degenerative processes, including vascular dysfunction [12,20,36]. To assess the HNE-induced oxidative stress in vascular endothelial cells, we analyzed ROS production using confocal microscopy.…”

Section: Resultsmentioning

confidence: 99%

“…These reactive aldehydes are known to cause redox disturbances and various degenerative processes, including the vascular dysfunction associated with aging [12,20,37]. It seems logical that HNE and HHE are the subjects of recent intensified studies investigating their roles in the modulation of cell signaling pathways and the induction of apoptosis [2,15,36]. HNE as a potent cytotoxic agent is a byproduct of n-6 fatty acid peroxidation [12,35], which can accumulate up to concentrations of 10 μM to 5 mM both in vivo and in vitro [8,33].…”

Section: Introductionmentioning

confidence: 99%

4-Hydroxynonenal Induces Endothelial Apoptosis through Mitochondrial Depolarization

Kang¹,

Lee²,

Kim³

et al. 2008

Journal of Life Science

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The 4-Hydroxynonenal (HNE) affects vascular dysfunctions probably through the interruption of the cellular redox balance. To better understand vascular abnormalities resulting from the accumulation of HNE, we delineated mechanism by which mitochondrial apoptosis occurs in the YPEN-1 endothelial cells. HNE treatment led to the loss of mitochondrial membrane potential (δΨm), resulting in the release of cytochrome c. Data showed decreased Bcl-2 and increased Bax protein levels in HNE-treated cells. NAC, a reactive oxygen species (ROS) scavenger, and penicillamine, the peroxynitrite scavenger, blocked HNE-mediated ROS generation, thereby thwarting the cytochrome c release and apoptosis. The treatment of the cells with zVAD-fmk, a broad range caspase inhibitor did not suppress HNE-induced apoptosis, suggesting that the apoptosis might be the possibility of caspase-independent process. Our findings delineate the underlying mechanism of the HNE induced endothelial apoptosis by triggering depolarization of mitochondria membrane potential that can lead to the deterioration of vasculature homeostasis and subsequent vascular dysfunction with aging.

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Role of Mitogen-activated Protein Kinases in 4-Hydroxy-2-nonenal-induced Actin Remodeling and Barrier Function in Endothelial Cells

Cited by 150 publications

References 60 publications

Src-mediated Tyrosine Phosphorylation of p47 in Hyperoxia-induced Activation of NADPH Oxidase and Generation of Reactive Oxygen Species in Lung Endothelial Cells

Src-mediated Tyrosine Phosphorylation of p47 in Hyperoxia-induced Activation of NADPH Oxidase and Generation of Reactive Oxygen Species in Lung Endothelial Cells

HNE increases HO-1 through activation of the ERK pathway in pulmonary epithelial cells

4-Hydroxynonenal Induces Endothelial Apoptosis through Mitochondrial Depolarization

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