Valproic acid downregulates heme oxygenase-1 independently of Nrf2 by increasing ubiquitination and proteasomal degradation

Jez, Mateusz; Cieśla, Maciej; Stępniewski, Jacek; Langrzyk, Agnieszka; Muchová, Lucie; Vı́tek, Libor; Józkowicz, Alicja; Dulak, Józef

doi:10.1016/j.bbrc.2017.02.041

Cited by 8 publications

(12 citation statements)

References 28 publications

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“…Therefore, we conclude that simvastatin-induced upregulation of HO-1 in HAoEC or HAoSMC is not associated with Nrf2/ARE system and simvastatin-induced upregulation of HMOX1 gene with simultaneous downregulation of HO-1 at the protein level might be associated other mechanisms such as posttransciptional regulation of HO-1 as it was shown in our recently published paper [ 8 ].…”

Section: Resultssupporting

confidence: 53%

“…Thus, we hypothesize that there is an additional regulation of HO-1 protein level. We cannot exclude that in patients with AAA, simvastatin influences ubiquitination and proteasomal degradation of HO-1, therefore regulating its expression directly on the protein level and independently of Nrf2 which we recently shown in human and murine cells by our group [ 8 ]. Moreover, as aneurysmal tissue is infiltrated by inflammatory cells, the effect of simvastatin may be masked.…”

Section: Discussionmentioning

confidence: 97%

“…The control of HO-1 expression occurs primarily at the transcriptional level and is mediated by different transcription factors such as nuclear factor kappa B (NF- κ B) and nuclear factor E2-related factor-2 (Nrf2) [ 7 ]. However, our recent studies indicated that HO-1 expression may be regulated not only at the mRNA level but also at the protein level by increased ubiquitination and proteasomal degradation of HO-1 and that this effect is independent of Nrf2 [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

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Simvastatin Treatment Upregulates HO‐1 in Patients with Abdominal Aortic Aneurysm but Independently of Nrf2

Piechota-Polańczyk

Kopacz

Klóska

et al. 2018

Oxidative Medicine and Cellular Longevity

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Heme oxygenase-1 (HO-1), encoded by HMOX1 gene and regulated by Nrf2 transcription factor, is a cytoprotective enzyme. Its deficiency may exacerbate abdominal aortic aneurysm (AAA) development, which is also often associated with hyperlipidemia. Beneficial effects of statins, the broadly used antilipidemic drugs, were attributed to modulation of Nrf2/HO-1 axis. However, the effect of statins on Nrf2/HO-1 pathway in patients with AAA has not been studied yet. We analyzed AAA tissue from patients treated with simvastatin (N = 28) or without statins (N = 14). Simvastatin treatment increased HO-1 protein level in AAA, both in endothelial cells (ECs) and in smooth muscle cells (SMCs), but increased Nrf2 localization was restricted only to vasa vasorum. Nrf2 target genes HMOX1, NQO1, and GCLM expression remained unchanged in AAA. In vitro studies showed that simvastatin raises HO-1 protein level slightly in ECs and to much higher extent in SMCs, which is not related to Nrf2/ARE activation, although HMOX1 expression is upregulated by simvastatin in both cell types. In conclusion, simvastatin-induced modulation of HO-1 level in ECs and SMCs in vitro is not related to Nrf2/ARE activity. Likewise, divergent HO-1 and Nrf2 localization together with stable expression of Nrf2 target genes, including HMOX1, in AAA tissue denotes Nrf2 independency.

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Section: Resultssupporting

confidence: 53%

Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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Simvastatin Treatment Upregulates HO‐1 in Patients with Abdominal Aortic Aneurysm but Independently of Nrf2

Piechota-Polańczyk

Kopacz

Klóska

et al. 2018

Oxidative Medicine and Cellular Longevity

Self Cite

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“…Notably, these proteins were downregulated in the NT group at all time points, and this decrease was inhibited in the DHMBA group. Therefore, de novo protein expression, translocation from the cytoplasm to the nucleus and other fractions [ 32 ], and protein decomposition [ 33 ] should all be ruled out. In fact, translocation of HO-1 into the nucleus enhances the transcriptional activity of AP-1 [ 32 ] and Nrf2 [ 33 ], and translocation of TRX-1 into the nucleus regulates the transcriptional activity of HIF1α [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

The Phenolic Antioxidant 3,5-dihydroxy-4-methoxybenzyl Alcohol (DHMBA) Prevents Enterocyte Cell Death under Oxygen-Dissolving Cold Conditions through Polyphyletic Antioxidant Actions

Fukai

Nakayabu

Ohtani

et al. 2021

JCM

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Cold preservation in University of Wisconsin (UW) solution is not enough to maintain the viability of the small intestine, due to the oxidative stress. The novel phenolic antioxidant 3,5-dihydroxy-4-methoxybenzyl alcohol (DHMBA) has dual properties to reduce oxidative stress, radical scavenging, and antioxidant protein induction, in other cells. This study was designed to determine whether DHMBA reduces cold preservation injury of enterocytes, and to identify the effector site. Enterocytes were subjected to 48-h cold preservation under atmosphere in UW solution (±DHMBA), and then returned to normal culture to replicate reperfusion of the small intestine after cold preservation. At the end of cold preservation (ECP) and at 1, 3, 6, and 72 h after rewarming (R1h, R3h, R6h, and R72h), we evaluated cell function and the injury mechanism. The results showed that DHMBA protected mitochondrial function mainly during cold preservation, and suppressed cell death after rewarming, as shown by the MTT, ATP, mitochondrial membrane potential, LDH, and lipid peroxidation assays, together with enhanced survival signals (PI3K, Akt, p70S6K) and induction of antioxidant proteins (HO-1, NQO-1, TRX-1). We found that DHMBA mitigates the cold-induced injury of enterocytes by protecting the mitochondria through direct and indirect antioxidative activities.

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“…HO-1 protein is regulated at various levels, including the occurrence of posttranslational modifications, such as phosphorylation and ubiquitination 41,42 . In addition, the protein stability of HO-1 is positively regulated by the 14-3-3-ζ protein 43 and downregulated by valproic acid, an anti-epileptic drug that inhibits histone deacetylases 44 .…”

Section: Discussionmentioning

confidence: 99%

SIAH2-mediated and organ-specific restriction of HO-1 expression by a dual mechanism

Chillappagari

Belapurkar

Möller

et al. 2020

Sci Rep

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The intracellular levels of the cytoprotective enzyme heme oxygenase-1 (HO-1) are tightly controlled. Here, we reveal a novel mechanism preventing the exaggerated expression of HO-1. The analysis of mice with a knock-out in the ubiquitin E3 ligase seven in absentia homolog 2 (SIAH2) showed elevated HO-1 protein levels in specific organs such as heart, kidney and skeletal muscle. Increased HO-1 protein amounts were also seen in human cells deleted for the SIAH2 gene. The higher HO-1 levels are not only due to an increased protein stability but also to elevated expression of the HO-1 encoding HMOX1 gene, which depends on the transcription factor nuclear factor E2-related factor 2 (NRF2), a known SIAH2 target. Dependent on its RING (really interesting new gene) domain, expression of SIAH2 mediates proteasome-dependent degradation of its interaction partner HO-1. Additionally SIAH2-deficient cells are also characterized by reduced expression levels of glutathione peroxidase 4 (GPX4), rendering the knock-out cells more sensitive to ferroptosis.Another HO-1 regulated process is ferroptosis, a regulated but non-apoptotic form of cell death that can be induced experimentally by compounds such as erastin 28 . Ferroptosis is characterized by high ROS levels derived from iron metabolism and lipid peroxidation. Depending on the stimulus and cell type, HO-1 can mitigate or enhance ferroptosis 19,29,30 . To test the effects of SIAH2 deletion on erastin-induced ferroptosis, wild-type and SIAH2-deficient cells were used. Two days after induction of ferroptosis, dead cells were aspirated off Scientific RepoRtS | (2020) 10:2268 | https://doi.

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Valproic acid downregulates heme oxygenase-1 independently of Nrf2 by increasing ubiquitination and proteasomal degradation

Cited by 8 publications

References 28 publications

Simvastatin Treatment Upregulates HO‐1 in Patients with Abdominal Aortic Aneurysm but Independently of Nrf2

Simvastatin Treatment Upregulates HO‐1 in Patients with Abdominal Aortic Aneurysm but Independently of Nrf2

The Phenolic Antioxidant 3,5-dihydroxy-4-methoxybenzyl Alcohol (DHMBA) Prevents Enterocyte Cell Death under Oxygen-Dissolving Cold Conditions through Polyphyletic Antioxidant Actions

SIAH2-mediated and organ-specific restriction of HO-1 expression by a dual mechanism

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