Oxidative stress-inducible lentiviral vectors for gene therapy

Hurttila, Hanna; Jk, Koponen; Kansanen, Emilia; Hk, Jyrkkänen; Kivelä, Annukka M.; Kylätie, R; Ylä‐Herttuala, Seppo; Levonen, Anna–Liisa

doi:10.1038/gt.2008.75

Cited by 56 publications

(37 citation statements)

References 46 publications

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“…Iron released from the HO-1 reaction may potentially act as a catalyst of deleterious pro-oxidant reactions, such as the metal-catalyzed Haber-Weiss cycle, or iron-dependent lipid peroxidation (79). Potential pro-oxidant effects of HO-1 or Scheme 2.…”

Section: Ho-1: Mechanisms Of Cytoprotectionmentioning

confidence: 99%

Heme Oxygenase-1/Carbon Monoxide

Ryter

Choi

2009

Am J Respir Cell Mol Biol

260

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Heme oxygenase-1 (HO-1), a ubiquitous inducible stress-response protein, serves a major metabolic function in heme turnover. HO activity cleaves heme to form biliverdin-IXa, carbon monoxide (CO), and iron. Genetic experiments have revealed a central role for HO-1 in tissue homeostasis, protection against oxidative stress, and in the pathogenesis of disease. Four decades of research have witnessed not only progress in elucidating the molecular mechanisms underlying the regulation and function of this illustrious enzyme, but also have opened remarkable translational applications for HO-1 and its reaction products. CO, once regarded as a metabolic waste, can act as an endogenous mediator of cellular signaling and vascular function. Exogenous application of CO by inhalation or pharmacologic delivery can confer cytoprotection in preclinical models of lung/vascular injury and disease, based on anti-apoptotic, antiinflammatory, and anti-proliferative properties. The bile pigments, biliverdin and bilirubin, end products of heme degradation, have also shown potential as therapeutics in vascular disease based on anti-inflammatory and anti-proliferative activities. Further translational and clinical trials research will unveil whether the HO-1 system or any of its reaction products can be successfully applied as molecular medicine in human disease.

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Section: Ho-1: Mechanisms Of Cytoprotectionmentioning

confidence: 99%

Heme Oxygenase-1/Carbon Monoxide

Ryter

Choi

2009

Am J Respir Cell Mol Biol

260

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“…16 h after treatment, luciferase activities were measured with Britelite Reporter Gene Assay (PerkinElmer Life Sciences) according to the manufacturer's instructions. Luciferase activities were normalized to ␤-galactosidase activities measured as described previously (26).…”

Section: Lc/ms Detection and Analysis Of Keap1mentioning

confidence: 99%

Electrophilic Nitro-fatty Acids Activate NRF2 by a KEAP1 Cysteine 151-independent Mechanism

Kansanen

Bonacci

Schöpfer

et al. 2011

Journal of Biological Chemistry

184

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Nitro-fatty acids (NOIn this study, we investigate the molecular mechanisms by which 9-and 10-nitro-octadec-9-enoic acid (OA-NO 2 ) activate the transcription factor Nrf2, focusing on the post-translational modifications of cysteines in the Nrf2 inhibitor Keap1 by nitroalkylation and its downstream responses. Of the two regioisomers, 9-nitrooctadec-9-enoic acid was a more potent ARE inducer than 10-nitro-octadec-9-enoic acid. (2), the enzyme xanthine oxidoreductase (3), and the transcription factor peroxisome proliferator-activated receptor ␥ (PPAR␥) (4). Moreover, NO 2 -FAs activate heat shock (5) and antioxidant response pathways (5, 6) via mechanisms that remain to be defined. Antioxidant response element (ARE)-regulated genes play an essential role in the protection against endogenous and exogenous stresses (7). The transcription factor nuclear factor E2-related factor-2 (Nrf2) can activate these genes via binding to AREs as a heterodimer with small Maf proteins (7). Under basal conditions, Nrf2 is bound to its inhibitor Kelch-like ECHassociated protein 1 (Keap1), which functions as an adaptor molecule in the Cul3-based E3 ligase complex. Nrf2 is then rapidly ubiquitinated and degraded (8, 9). During periods when cellular concentrations of oxidative or electrophilic species are elevated, the interaction of Nrf2 with the ubiquitin ligase complex is disrupted, enabling the escape of Nrf2 from degradation, its nuclear translocation, and transactivation of target genes.Keap1 is a Cys-rich protein with 27 Cys residues in the human and 25 Cys residues in the murine protein. Keap1 has four functional domains: the Bric-a-Brac, tramtrack, broad complex (BTB) domain, the intervening region (IVR), the Kelch domain (also known as the double glycine repeat), and the C-terminal region. Alkylation or oxidation of Keap1 Cys residues, predominantly within the IVR, leads to the inactivation of Keap1 and is the central mechanism for the activation of Nrf2 (10 -12). A number of studies utilizing mass spectrometry (MS) analysis show that electrophilic inducers of Nrf2 modify several different Cys residues in recombinant Keap1. These data indi-* This work was supported, in whole or in part, by National Institutes of Health BTB, Bric-a-Brac, tramtrack, broad complex; IVR, intervening region; 15d-PGJ 2 , 15-deoxy-⌬12,14-prostaglandin J 2 ; HEK, human embryonic kidney; ␤-ME, ␤-mercaptoethanol; OA-NO 2 , 9-and 10-nitro-octadec-9-enoic acid; 9-OA-NO 2 , 9-nitro-octadec-9-enoic acid; 10-OA-NO 2 , 10-nitro-octadec-9-enoic acid; LNO 2 , 9-, 10-, 12-, or 13-nitro-octadeca-9,12-dienoic acid.

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“…Although some endogenous cellular elements that respond to exogenous signals or stress have been adapted to HIV-1-and EIAV-derived lentiviral vectors (Beutelspacher et al, 2005;Hurttila et al, 2008;Parker et al, 2009), the pleiotropic effects exerted by the inducing agent would be a drawback in a human therapeutic context (Fussenegger, 2001).…”

Section: Other Regulatable Systemsmentioning

confidence: 99%