Epigenetic Regulation of Oxidative Stress in Ischemic Stroke

Abstract

The prevalence and incidence of stroke rises with life expectancy. However, except for the use of recombinant tissue-type plasminogen activator, the translation of new therapies for acute stroke from animal models into humans has been relatively unsuccessful. Oxidative DNA and protein damage following stroke is typically associated with cell death. Cause-effect relationships between reactive oxygen species and epigenetic modifications have been established in aging, cancer, acute pancreatitis, and fatty liver disease. In addition, epigenetic regulatory mechanisms during stroke recovery have been reviewed, with focuses mainly on neural apoptosis, necrosis, and neuroplasticity. However, oxidative stress-induced epigenetic regulation in vascular neural networks following stroke has not been sufficiently explored. Improved understanding of the epigenetic regulatory network upon oxidative stress may provide effective antioxidant approaches for treating stroke. In this review, we summarize the epigenetic events, including DNA methylation, histone modification, and microRNAs, that result from oxidative stress following experimental stroke in animal and cell models, and the ways in which epigenetic changes and their crosstalk influence the redox state in neurons, glia, and vascular endothelial cells, helping us to understand the foregone and vicious epigenetic regulation of oxidative stress in the vascular neural network following stroke.

The epigenetic landscape related to reactive oxygen species formation in the cardiovascular system

“…In the working skeletal muscle, NOX2‐dependent ROS generation has been reported to lead to nuclear efflux of HDAC4 and HDAC5 and muscle remodelling (Liu et al , ). Similarly, ROS increased nuclear exit of HDAC4/5 in angiotensin‐II‐induced vascular remodelling and cerebral ischaemic injury (Wang et al , ; Zhao et al , ) (Figure ).…”

“…For example, hypermethylation of the gene encoding the transcription factor KLF4 decreased the expression of endothelial NOS under these conditions (Dunn et al , ). While these studies suggest that ROS can induce specific hypermethylation by up‐regulating DNMTs, several studies found that ROS can also affect DNA methylation by modulating the DNA recruitment of DNMTs without affecting DNMT expression (Lim et al , ; Zhao et al , ). For example, ROS induced Snail, which was required to recruit DNMT1 to the E‐cadherin promoter for hypermethylation (Lim et al , ).…”

“…Further, arsenite or hypoxia up‐regulated the histone H3K9 methyltransferase G9a and the repressive mark H3K9me2 (Chervona and Costa, ) (Figure ), a mechanism which has been associated with the adverse outcome of stroke (Zhao et al , ). Hypoxia also increased G9a‐mediated H3K9me2 levels in the promoters of neprilysin or dihydrofolate reductase (Chervona and Costa, ), mechanisms possibly involved in Alzheimer's disease (Wang et al , ) or pulmonary hypertension (Chalupsky et al , ), respectively.…”

“…In contrast, treatment of neurons with H 2 O 2 promoted HDAC4 translocation from the cytoplasm to the nucleus, leading to decreased PPARγ transcription, thus rendering neurons more vulnerable to H 2 O 2 insult (Zhao et al , ). In models of redox‐associated pulmonary hypertension, increased nuclear accumulation of HDAC4 and HDAC5 was associated with decreased levels of miR‐424 and miR‐503, two miRNAs involved in maintenance of pulmonary vascular homeostasis, while application of a class II HDAC inhibitor prevented these responses (Kim et al , ) (Figure ).…”

The role of 5‐hydroxymethylcytosine in mitochondria after ischemic stroke

“…5hmC, which is produced from the oxidation of 5mC by Tet enzymes (Ko et al, ; Tahiliani et al, ), exists in genomic DNA (Penn, Suwalski, O'Riley, Bojanowski, & Yura, ), RNA (Huber et al, ), and mitochondrial DNA (mtDNA) (Shock, Thakkar, Peterson, Moran, & Taylor, ). Epigenetic modifications are emerging as an important mechanism for neuronal survival versus death after ischemic brain injury (Jhelum, Karisetty, Kumar, & Chakravarty, ; Zhao, Han, Ji, & Luo, ). Previous studies with colorectal cancer cells have shown that mtDNA methylation directly influences the mtDNA copy number and further alters the cell cycle, apoptosis, and proliferation (Tong et al, 2017).…”