NO signaling in ARE-mediated gene expression
ABSTRACT Nitric oxide (NO) and peroxynitrite, which serve as cell signal molecules, activate the antioxidant response element (ARE) for the induction of phase II antioxidant enzymes as an adaptive response. The reactive nitrogen species plays an essential role in Nrf2 activation and Nrf2 binding to the ARE present in the target genes. In this chapter, we describe the system by which the NO signaling pathway regulates ARE-mediated gene expression, which includes immunochemical assessment and gel shift analysis of Nrf2 activation.
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- "Moreover, peroxynitrite , another reactive nitrogen species, produces the induction of the Nrf2–Keap1 pathway (Kang et al. 2002). Park and Kim (2005) showed that treatment with 3- morpholinosydnonimene hypochloride (SIN-1), a peroxynitrite-induced compound, generates Nrf2 translocation to the nucleus and its coupling to ARE. Similar to NO, this activation protects cells against peroxynitrite-induced apoptosis (Li et al. 2006). "
ABSTRACT: Atmospheric pollution is a worldwide problem. Exposure to atmospheric pollutants causes toxic cellular effects. One of the mechanisms of toxicity by these pollutants is the promotion of oxidative stress. Several signaling pathways control cellular redox homeostasis. In this respect, nuclear factor erythroid 2-related factor 2 (Nrf2) is a crucial transcription factor in the cell's response to oxidative stress. In cellular animal models, exposure to atmospheric pollutants activates Nrf2, attenuating its toxic and even its carcinogenic effects. Therefore, we have reviewed the scientific literature in order to indicate that air pollutants, such as particulate matter, polycyclic aromatic hydrocarbons, and gaseous matter, are Nrf2 pathway inductors, triggering self-defense through the establishment of proinflammatory and antioxidant responses. Exposure to reactive molecules as atmospheric pollutants causes the activation of Nrf2 and the subsequent regulation of the expression of cytoprotective and detoxifying enzymes, as well as antioxidants. Moreover, induction of Nrf2 prior to exposure reduces the harmful effects of pollutants. The present article discusses the protective role of the Nrf2 pathway against different atmospheric pollutant insults. Nrf2 regulates the expression of numerous cytoprotective genes that function to detoxify reactive species produced during atmospheric pollutant metabolic reactions. From the papers highlighted in this review, we conclude that Nrf2 has an important role in the defense against atmospheric pollutant-induced toxicity. Further studies are needed to understand the signaling events that turn on the system in response to atmospheric pollutant stress. This could allow for the possibility of targeting the pathway for prevention benefits in the near future.Environmental Science and Pollution Research 05/2009; 17(2):369-82. DOI:10.1007/s11356-009-0140-6 · 2.76 Impact Factor
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ABSTRACT: Increased generation of reactive oxygen species (ROS) in vascular diseases such as atherosclerosis, diabetes, chronic renal failure and preeclampsia readily leads to impaired endothelium-dependent relaxation and vascular injury. To counteract ROS- and electrophile-mediated injury, cells can induce a number of genes encoding phase II detoxifying enzymes and antioxidant proteins. A cis-acting transcriptional regulatory element, designated as antioxidant response element (ARE) or electrophile response element (EpRE), mediates the transcriptional activation of genes such as heme oxygenase-1, gamma-glutamylcysteine synthethase, thioredoxin reductase, glutathione-S-transferase and NAD(P)H:quinone oxidoreductase. Other antioxidant enzymes such as superoxide dismutase and catalase and non-enzymatic scavengers such as glutathione are also involved in scavenging ROS. Nuclear factor-erythroid 2-related factor 2 (Nrf2), a member of the Cap nno Collar family of basic region-leucine zipper (bZIP) transcription factors, plays an important role in ARE-mediated antioxidant gene expression. Kelch-like ECH-associated protein-1 (Keap1) normally sequesters Nrf2 in the cytoplasm in association with the actin cytoskeleton, but upon oxidation of cysteine residues Nrf2 dissociates from Keap1, translocates to the nucleus and binds to ARE sequences leading to transcriptional activation of antioxidant and phase II detoxifying genes. Protein kinase C (PKC), mitogen-activated protein kinases (MAPKs) and phosphotidylinositol 3-kinase (PI3K) have been implicated in the regulation of Nrf2/ARE signaling. We here review the evidence that the Nrf2/ARE signaling pathway plays an important role in vascular homeostasis and the defense of endothelial and smooth muscle cells against sustained oxidative stress associated with diseases such as atherosclerosis and preeclampsia.Sheng li xue bao: [Acta physiologica Sinica] 05/2007; 59(2):117-27.
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ABSTRACT: LCY-2-CHO has anti-inflammatory actions on macrophages. To understand its therapeutic implication in atherosclerosis, we examined its effects on the expressions of anti-inflammatory and inflammatory proteins in cultured rat aortic vascular smooth muscle cells (VSMC). LCY-2-CHO is able to induce heme oxygenase-1 (HO-1) protein expression through a transcriptional action. The HO-1 inducting effect of LCY-2-CHO was inhibited by SB203580, N(G)-nitro-l-arginine methylester (l-NAME), and wortmannin, but was not affected by U0126 or SP600125. In accordance LCY-2-CHO increased protein phosphorylation of p38, Akt, and eNOS. Nrf2 is a transcription factor essential for HO-1 gene induction and we showed that LCY-2-CHO is able to cause Nrf2 nuclear translocation and this action depends on p38, Akt and eNOS. In addition to induce anti-inflammatory HO-1, LCY-2-CHO reduced interleukin-1beta (IL-1beta)-induced inflammatory mediators, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), growth-related oncogene protein-alpha (GRO-alpha), and interleukin-8 (IL-8). Inhibitory effect on IL-1beta-mediated NF-kappaB activation was evidenced by the diminishment of IkappaB kinase (IKK) phosphorylation and IkappaBalpha degradation. In contrast, IL-1beta-mediated ERK and JNK activations were not changed by LCY-2-CHO, while p38 activation by IL-1beta and LCY-2-CHO displayed the non-additivity. Taken together, given the overall anti-inflammatory properties of LCY-2-CHO in VSMC, in terms to induce HO-1 gene expression and inhibit inflammatory gene expression, these results highlight the therapeutic potential of LCY-2-CHO in atherosclerosis.Biochemical Pharmacology 08/2007; 74(2):298-308. DOI:10.1016/j.bcp.2007.04.008 · 4.65 Impact Factor