Epigenetic mechanisms and potential therapeutic targets in stroke

Morris-Blanco, Kahlilia C; Chokkalla, Anil K; Arruri, Vijay Kumar; Jeong, Soomin; Probelsky, Samantha M; Vemuganti, Raghu

doi:10.1177/0271678x221116192

Cited by 12 publications

(9 citation statements)

References 151 publications

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“…9,10 REST-dependent epigenetic remodeling of several genes in neurons plays a critical role in ischemia-induced neuronal death. 44,45 The interaction of FosDT with coREST and Sin3a can be reduced through the FosDT knockdown, suggesting that FosDT scaffolding is an essential component for the activity of the REST complex. 9,10 Stroke and neurodegenerative diseases lead to REST induction in CNS, which is known to aggravate neuronal injury; REST knockdown decreases brain damage and improves neurologic recovery after stroke.…”

Section: Discussionmentioning

confidence: 99%

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Post-stroke brain can be protected by modulating the lncRNA FosDT

Mehta,

Chelluboina,

Morris-Blanco

et al. 2023

J Cereb Blood Flow Metab

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We previously showed that knockdown or deletion of Fos downstream transcript (FosDT; a stroke-induced brain-specific long noncoding RNA) is neuroprotective. We presently tested the therapeutic potential of FosDT siRNA in rodents subjected to transient middle cerebral artery occlusion (MCAO) using the Stroke Treatment Academic Industry Roundtable criteria, including sex, age, species, and comorbidity. FosDT siRNA (IV) given at 30 min of reperfusion significantly improved motor function recovery (rotarod test, beam walk test, and adhesive removal test) and reduced infarct size in adult and aged spontaneously hypertensive rats of both sexes. FosDT siRNA administered in a delayed fashion (3.5 h of reperfusion following 1 h transient MCAO) also significantly improved motor function recovery and decreased infarct volume. Furthermore, FosDT siRNA enhanced post-stroke functional recovery in normal and diabetic mice. Mechanistically, FosDT triggered post-ischemic neuronal damage via the transcription factor REST as REST siRNA mitigated the enhanced functional outcome in FosDT−/− rats. Additionally, NF-κB regulated FosDT expression as NF-κB inhibitor BAY 11-7082 significantly decreased post-ischemic FosDT induction. Thus, FosDT is a promising target with a favorable therapeutic window to mitigate secondary brain damage and facilitate recovery after stroke regardless of sex, age, species, and comorbidity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Post-stroke brain can be protected by modulating the lncRNA FosDT

Mehta,

Chelluboina,

Morris-Blanco

et al. 2023

J Cereb Blood Flow Metab

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“…Stroke is a leading cause of death worldwide and is associated with long‐term disability 1 . However, the clinical treatment of stroke is limited.…”

Section: Introductionmentioning

confidence: 99%

“…Stroke is a leading cause of death worldwide and is associated with long‐term disability. 1 However, the clinical treatment of stroke is limited. Remote ischemic pre‐conditioning (RIPC) is ischemia that is performed in one organ and protects against subsequent prolonged ischemia in another distant organ.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of the JAK2/STAT3 pathway and cell cycle re‐entry contribute to the protective effect of remote ischemic pre‐conditioning of rat hindlimbs on cerebral ischemia/reperfusion injury

et al. 2022

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Aims Remote ischemic pre‐conditioning (RIPC) protects against ischemia/reperfusion (I/R) injury. However, the mechanisms underlying this protection remain unclear. In the present study, we investigated the role of Janus‐activated kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway and cell cycle arrest, and their relationship with neuronal apoptosis following RIPC. Methods A rat cerebral I/R injury model was induced by middle cerebral artery occlusion (MCAO), and AG490 was used to investigate the mechanisms of RIPC. p‐JAK2‐, p‐STAT3‐, cyclin D1‐, and cyclin‐dependent kinase 6 (CDK6) expression was assessed by Western blotting and immunofluorescence staining. Results RIPC reduced the infarct volume, improved neurological function, and increased neuronal survival. Furthermore, p‐JAK2 and p‐STAT3 were detected during the initial phase of reperfusion; the expression levels were significantly increased at 3 and 24 h after reperfusion and were suppressed by RIPC. Additionally, the MCAO‐induced upregulation of the cell cycle regulators cyclin D1 and CDK6 was ameliorated by RIPC. Meanwhile, cyclin D1 and CDK6 were colocalized with p‐STAT3 in the ischemic brain. Conclusion RIPC ameliorates the induction of the JAK2/STAT3 pathway and cell cycle regulators cyclin D1 and CDK6 by MCAO, and this net inhibition of cell cycle re‐entry by RIPC is associated with downregulation of STAT3 phosphorylation.

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“…4,5 Thus, numerous studies have explored the impact of different genetic, epigenetic, and molecular factors on poststroke outcomes. [6][7][8][9][10] Among these factors, recent research has highlighted mitochondrial DNA copy number (mtDNA-CN) as a promising predictor of poststroke outcome. 9,10 mtDNA-CN measures the number of mitochondrial genomes per cell and is linked to the activity of mitochondrial respiratory enzymes and the production of ATP.…”

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Subtype-Specific Association of Mitochondrial DNA Copy Number With Poststroke/TIA Outcomes in 10 241 Patients in China

Jiang,

Cheng,

Shi

et al. 2024

Stroke

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BACKGROUND: Mitochondrial DNA copy number (mtDNA-CN) is associated with the severity and mortality in patients with stroke, but the associations in different stroke subtypes remain unexplored. METHODS: We conducted an observational prospective cohort analysis on patients with ischemic stroke or transient ischemic attack enrolled in the Third China National Stroke Registry. We applied logistic models to assess the association of mtDNA-CN with functional outcome (modified Rankin Scale score, 3–6 versus 0–2) and Cox proportional hazard models to assess the association with stroke recurrence (treating mortality as a competing risk) and mortality during a 12-month follow-up, adjusting for sex, age, physical activity, National Institutes of Health Stroke Scale at admission, history of stroke and peripheral artery disease, small artery occlusion, and interleukin-6. Subgroup analyses stratified by age and stroke subtypes were conducted. RESULTS: The Third China National Stroke Registry enrolled 15 166 patients, of which 10 241 with whole-genome sequencing data were retained (mean age, 62.2 [SD, 11.2] years; 68.8% men). The associations between mtDNA-CN and poststroke/transient ischemic attack outcomes were specific to patients aged ≤65 years, with lower mtDNA-CN significantly associated with stroke recurrence in 12 months (subdistribution hazard ratio, 1.15 per SD lower mtDNA-CN [95% CI, 1.04–1.27]; P =5.2×10 −3 ) and higher all-cause mortality in 3 months (hazard ratio, 2.19 [95% CI, 1.41–3.39]; P =5.0×10 −4 ). Across subtypes, the associations of mtDNA-CN with stroke recurrence were specific to stroke of undetermined cause (subdistribution hazard ratio, 1.28 [95% CI, 1.11–1.48]; P =6.6×10 −4 ). In particular, lower mtDNA-CN was associated with poorer functional outcomes in stroke of undetermined cause patients diagnosed with embolic stroke of undetermined source (odds ratio, 1.53 [95% CI, 1.20–1.94]; P =5.4×10 −4 ), which remained significant after excluding patients with recurrent stroke (odds ratio, 1.49 [95% CI, 1.14–1.94]; P =3.0×10 −3 ). CONCLUSIONS: Lower mtDNA-CN is associated with higher stroke recurrence rate and all-cause mortality, as well as poorer functional outcome at follow-up, among stroke of undetermined cause, embolic stroke of undetermined source, and younger patients.

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Epigenetic mechanisms and potential therapeutic targets in stroke

Cited by 12 publications

References 151 publications

Post-stroke brain can be protected by modulating the lncRNA FosDT

Post-stroke brain can be protected by modulating the lncRNA FosDT

Inhibition of the JAK2/STAT3 pathway and cell cycle re‐entry contribute to the protective effect of remote ischemic pre‐conditioning of rat hindlimbs on cerebral ischemia/reperfusion injury

Subtype-Specific Association of Mitochondrial DNA Copy Number With Poststroke/TIA Outcomes in 10 241 Patients in China

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