Differential Responses of the Nrf2-Keap1 System to Laminar and Oscillatory Shear Stresses in Endothelial Cells

Hosoya, Takamitsu; Maruyama, Atsushi; Kang, Moon Il; Kawatani, Yukie; Shibata, Takahiro; Uchida, Koji; Itoh, Ken; Yamamoto, Masayuki

doi:10.1074/jbc.m502551200

Cited by 205 publications

(157 citation statements)

References 59 publications

(47 reference statements)

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“…Previous studies have demonstrated that both OSS and LSS can induce nuclear accumulation of Nrf2 in ECs, but only LSS can enhance Nrf2 binding to the NQO1 ARE in EC nuclei (15). This finding suggests the presence of certain mediator(s) that could be induced by OSS to prevent Nrf2 binding to the NQO1 ARE.…”

Section: Discussionmentioning

confidence: 63%

Role of histone deacetylases in transcription factor regulation and cell cycle modulation in endothelial cells in response to disturbed flow

Lee

Lin

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

134

121

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Vascular endothelial cells (ECs) are exposed to different flow patterns (i.e., disturbed vs. laminar), and the associated oscillatory shear stress (OSS) or pulsatile shear stress (PSS) lead to differential responses. We investigated the roles of class I and II histone deacetylases (HDAC-1/2/3 and HDAC-5/7, respectively) in regulating NF-E2-related factor-2 (Nrf2) and Krüppel-like factor-2 (KLF2), two transcription factors governing many shear-responsive genes, and the cell cycle in ECs in response to OSS. Application of OSS (0.5 ± 4 dynes/cm 2 ) to cultured ECs sustainably up-regulated class I and II HDACs and their nuclear accumulation, whereas PSS (12 ± 4 dynes/cm 2 ) induced phosphorylation-dependent nuclear export of class II HDACs. En face immunohistochemical examination of rat aortic arch and experimentally stenosed abdominal aorta revealed high HDAC-2/3/5 levels in ECs in areas exposed to disturbed flow. OSS induced the association of HDAC-1/2/3 with Nrf2 and HDAC-3/ 5/7 with myocyte enhancer factor-2; deacetylation of these factors led to down-regulation of antioxidant gene NAD(P)H quinone oxidoreductase-1 (NQO1) and KLF2. HDAC-1/2/3-and HDAC-3/5/7-specific small interfering RNAs eliminated the OSS-induced downregulation of NQO1 and KLF2, respectively. OSS up-regulated cyclin A and down-regulated p21 CIP1 in ECs and induced their proliferation; these effects were mediated by HDAC-1/2/3. Intraperitoneal administration of the class I-specific HDAC inhibitor valproic acid into bromodeoxyuridine (BrdU)-infused rats inhibited the increased EC uptake of BrdU at poststenotic sites. The OSS-induced HDAC signaling and EC responses are mediated by phosphatidylinositol 3-kinase/Akt. Our findings demonstrate the important roles of different groups of HDACs in regulating the oxidative, inflammatory, and proliferative responses of ECs to disturbed flow with OSS.epigenetics | mechanotransduction | transcriptional regulation

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Section: Discussionmentioning

confidence: 63%

Role of histone deacetylases in transcription factor regulation and cell cycle modulation in endothelial cells in response to disturbed flow

Lee

Lin

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

134

121

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“…17 15d-PGJ 2 is a lipid oxidation product derived from the cyclooxygenase pathway, and it has been shown to be produced during inflammation 22 and shear stress. 23,24 It is also a potent inducer of Nrf2. 17,19 In HUVECs, the reporter gene expression of all constructs was increased by 15d-PGJ 2 ( Figure 2c).…”

Section: Developing and Testing Of Oxidative Stress-inducible Plasmidmentioning

confidence: 99%

Oxidative stress-inducible lentiviral vectors for gene therapy

Hurttila

Kansanen

et al. 2008

Gene Ther

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Oxidative stress is important in several pathologies, including cardiovascular diseases such as atherosclerosis and cardiac ischemia-reperfusion injury. An important mechanism for adaptation to oxidative stress is induction of genes through the antioxidant response element (ARE), which regulates the expression of antioxidant and cytoprotective genes via the transcription factor Nrf2 (nuclear factor E2-related factor 2). As Nrf2-regulated genes are induced during oxidant stress occurring, for example, in reperfusion after ischemia, we took a novel approach to exploit ARE for the development of oxidative stress-inducible gene therapy vectors. To this end, one, two or three ARE-containing regions from human NAD(P)H:quinone oxidoreductase-1, glutamate-cysteine ligase modifier subunit and mouse heme oxygenase-1 were cloned into a vector expressing luciferase under a minimal SV40 promoter. The construct, which was the most responsive to ARE-inducing agents, was chosen for further studies in which a lentiviral vector was produced for an efficient transfer to endothelial cells. Heme oxygenase-1 (HO-1), which has well-characterized anti-inflammatory properties, was used as the therapeutic transgene. In human endothelial cells, AREdriven HO-1 overexpression inhibited nuclear factor-kB activation and subsequent vascular cell adhesion molecule-1 expression induced by tumor necrosis factor-a. We conclude that the ARE element is a promising alternative for the development of oxidative stress-inducible gene therapy vectors.

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“…15d-PGJ 2 is a ligand of PPARc (195) and thereby acts as a repressor of LPS-stimulated AP-1, STAT1, and NF-jB activation (402). Being a strong electrophile, 15d-PGJ 2 can react with susceptible cysteines in a set of cytosolic and nuclear proteins (422), one of them being Keap1 (189). By targeting Keap1, 15d-PGJ 2 activates Nrf2 and, thus, initiates gene transcription with an overall anti-inflammatory result (see sections III.B and III.D) (Fig.…”

Section: E Termination Of Nf-kb Signalingmentioning

confidence: 99%

Basic Principles and Emerging Concepts in the Redox Control of Transcription Factors

Brigelius‐Flohé

Flohé

2011

Antioxidants & Redox Signaling

514

442

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Convincing concepts of redox control of gene transcription have been worked out for prokaryotes and lower eukaryotes, whereas the knowledge on complex mammalian systems still resembles a patchwork of poorly connected findings. The article, therefore, reviews principles of redox regulation with special emphasis on chemical feasibility, kinetic requirements, specificity, and physiological context, taking well investigated mammalian transcription factor systems, nuclear transcription factor of bone marrow-derived lymphocytes (NFjB), and kelch-like ECH-associated protein-1 (Keap1)/Nrf2, as paradigms. Major conclusions are that (i) direct signaling by free radicals is restricted to O 2 -and NO and can be excluded for fast reacting radicals such as OH, OR, or Cl ; (ii) oxidant signals are H 2 O 2 , enzymatically generated lipid hydroperoxides, and peroxynitrite; (iii) free radical damage is sensed via generation of Michael acceptors; (iv) protein thiol oxidation/alkylation is the prominent mechanism to modulate function; (v) redox sensors must be thiol peroxidases by themselves or proteins with similarly reactive cysteine or selenocysteine (Sec) residues to kinetically compete with glutathione peroxidase (GPx)-and peroxiredoxin (Prx)-type peroxidases or glutathione-S-transferases, respectively, a postulate that still has to be verified for putative mammalian sensors. S-transferases and Prxs are considered for system complementation. The impact of NF-jB and Nrf2 on hormesis, management of inflammatory diseases, and cancer prevention is critically discussed. Antioxid. Redox Signal. 15, 2335-2381.

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Differential Responses of the Nrf2-Keap1 System to Laminar and Oscillatory Shear Stresses in Endothelial Cells

Cited by 205 publications

References 59 publications

Role of histone deacetylases in transcription factor regulation and cell cycle modulation in endothelial cells in response to disturbed flow

Role of histone deacetylases in transcription factor regulation and cell cycle modulation in endothelial cells in response to disturbed flow

Oxidative stress-inducible lentiviral vectors for gene therapy

Basic Principles and Emerging Concepts in the Redox Control of Transcription Factors

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