Exendin-4 induces extracellular-superoxide dismutase through histone H3 acetylation in human retinal endothelial cells

Yasuda, Hiroyuki; Ohashi, Atsuko; Nishida, Shohei; Kamiya, Tetsuro; Suwa, Tetsuya; Hara, Hirokazu; Takeda, Jun; Itoh, Yoshinori; Adachi, Tetsuo

doi:10.3164/jcbn.16-26

Cited by 24 publications

(22 citation statements)

References 50 publications

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“…(27) We showed that the CpG site at EC-SOD promoter regions −452 to −207 in fibroblasts was unmethylated, whereas it was methylated in human retinal endothelial cells (HRECs), which weakly express EC-SOD. (40) A PCR analysis using McrBC showed that the EC-SOD promoter region from –729 to +51 in HRECs was digested by McrBC, while amplification in fibroblasts was resistant to McrBC (Fig. 1B).…”

Section: Resultsmentioning

confidence: 97%

Tumor necrosis factor-α decreases EC-SOD expression through DNA methylation

Morisawa

Yasuda

Kamiya

et al. 2017

J. Clin. Biochem. Nutr.

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Extracellular-superoxide dismutase (EC-SOD) is a secreted antioxidative enzyme, and its presence in vascular walls may play an important role in protecting the vascular system against oxidative stress. EC-SOD expression in cultured cell lines is regulated by various cytokines including tumor necrosis factor-α (TNF-α). TNF-α is a major mediator of pathophysiological conditions and may induce or suppress the generation of various types of mediators. Epigenetics have been defined as mitotically heritable changes in gene expression that do not affect the DNA sequence, and include DNA methylation and histone modifications. The results of the present study demonstrated that TNF-α significantly decreased EC-SOD level in fibroblasts with an accompanying increase in methylated DNA. In DNA methylation and demethylation, cytosine is methylated to 5-methylcytosine (5mC) by DNA methyltransferase (DNMT), and 5mC is then converted to 5-hydroxymethylcytosine (5hmC) and cytosine in a stepwise manner by ten-eleven translocation methylcytosine dioxygenases (TETs). However, DNMT did not participate in TNF-α-induced DNA methylation within the EC-SOD promoter region. On the other hand, TNF-α significantly suppressed TET1 expression and EC-SOD mRNA levels were decreased by the silencing of TET1 in fibroblasts. These results demonstrate that the down-regulation of EC-SOD by TNF-α is regulated by DNA methylation through reductions in TET1.

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Section: Resultsmentioning

confidence: 97%

Tumor necrosis factor-α decreases EC-SOD expression through DNA methylation

Morisawa

Yasuda

Kamiya

et al. 2017

J. Clin. Biochem. Nutr.

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“…Additionally, resveratrol inhibits axonal degeneration in Wallerian degeneration mice by activating SIRT2 (NAD-dependent tubulin deacetylase) [ 63 ]. Exendin-4 induces extracellular superoxide dismutase to combat oxidative stress through acetylation of histone H3 [ 64 ]. Interestingly, it was reported that autophagy is activated in both the early and duration of degenerating axons after SCI [ 65 ], indicating that autophagy could potentially represent a therapeutic target to reduce axonal degeneration in CNS injury.…”

Section: Discussionmentioning

confidence: 99%

Liraglutide activates autophagyviaGLP-1R to improve functional recovery after spinal cord injury

et al. 2017

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Therapeutics used to treat central nervous system (CNS) injury are designed to promote axonal regeneration and inhibit cell death. Previous studies have shown that liraglutide exerts potent neuroprotective effects after brain injury. However, little is known if liraglutide treatment has neuroprotective effects after spinal cord injury (SCI). This study explores the neuroprotective effects of liraglutide and associated underlying mechanisms. Our results showed that liraglutide could improve recovery after injury by decreasing apoptosis as well as increasing microtubulin acetylation, and autophagy. Autophagy inhibition with 3-methyladenine (3-MA) partially reversed the preservation of spinal cord tissue and decreased microtubule acetylation and polymerization. Additionally, siRNA knockdown of GLP-1R suppressed autophagy and reversed mTOR inhibition induced by liraglutide in vitro , indicating that GLP-1R regulates autophagic flux. GLP-1R knockdown ameliorated the mTOR inhibition and autophagy induction seen with liraglutide treatment in PC12 cells under H 2 O 2 stimulation. Taken together, our study demonstrated that liraglutide could reduce apoptosis, improve functional recovery, and increase microtubule acetylation via autophagy stimulation after SCI. GLP-1R was associated with both the induction of autophagy and suppression of apoptosis in neuronal cultures.

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“…In this study, acetylated H3K9 was shown to be decreased in the promoter of Glut2, a glucose transporter important for maintaining glucose homeostasis (136,137), and could be reversed by treatment with the diabetic inhibitor exendin-4 (135). Related to this, a report showed that exendin-4 can protect against diabetic retinopathy by inducing acetylation of histone H3 at the SOD3 promoter to drive its expression in endothelial cells (138). Further, reports from Spallotta et al and Melchionna et al showed that when treated with HDAC inhibitors, mice exhibited increased keratinocyte proliferation and improved wound healing (139,140).…”

Section: Histone Modificationsmentioning

confidence: 63%

Targeting epigenetic mechanisms in diabetic wound healing

Dekker

Davis

Kunkel

et al. 2019

Translational Research

171

121

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Impaired wound healing is a major secondary complication of type 2 diabetes that often results in limb loss and disability. Normal tissue repair progresses through discrete phases including hemostasis, inflammation, proliferation, and remodeling. In diabetes, normal progression through these phases is impaired resulting in a sustained inflammatory state and dysfunctional epithelialization in the wound. Due to their plasticity, macrophages play a critical role in the transition from the inflammation phase to the proliferation phase. Diabetes disrupts macrophage function by impairing monocyte recruitment to the wound, reducing phagocytosis, and prohibiting the transition of inflammatory macrophages to an anti-inflammatory state. Diabetes also impedes keratinocyte and fibroblast function during the later phases resulting in impaired epithelialization of the wound. Several recent studies suggest that altered epigenetic regulation of both immune and structural cells in wounds may influence cell phenotypes and healing, particularly in pathologic states, such as diabetes. Specifically, it has been shown that macrophage plasticity during wound repair is partly regulated epigenetically and that diabetes alters this epigenetic regulation and contributes to a sustained inflammatory state. Epigenetic regulation is also known to regulate keratinocyte and fibroblast function during wound repair. In this review, we provide an introduction to the epigenetic mechanisms that regulate tissue repair and highlight recent findings that demonstrate how epigenetic events are altered during the course of diabetic wound healing.

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Exendin-4 induces extracellular-superoxide dismutase through histone H3 acetylation in human retinal endothelial cells

Cited by 24 publications

References 50 publications

Tumor necrosis factor-α decreases EC-SOD expression through DNA methylation

Tumor necrosis factor-α decreases EC-SOD expression through DNA methylation

Liraglutide activates autophagyviaGLP-1R to improve functional recovery after spinal cord injury

Targeting epigenetic mechanisms in diabetic wound healing

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