Potential Roles of HDAC Inhibitors in Mitigating Ischemia-induced Brain Damage and Facilitating Endogenous Regeneration and Recovery

Fessler, Emily; Chibane, Fairouz L.; Wang, Zhifei; Chuang, De‐Maw

doi:10.2174/1381612811319280009

Cited by 75 publications

(53 citation statements)

References 186 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SUMOylation appears to provide a mechanism for ischemic tolerance (49). Interestingly, HDAC inhibitors have been shown to be protective in pre-clinical models of ischemic brain injury and in models of ischemic cardiomyopathy (50–53). Based on our findings, it is possible that at least a portion of the observed protective effects of HDAC inhibitors in the setting of ischemia are due to stimulation of SUMOylation.…”

Section: Discussionmentioning

confidence: 99%

Class I HDAC inhibition stimulates cardiac protein SUMOylation through a post-translational mechanism

Blakeslee

Wysoczynski

Fritz

et al. 2014

Cellular Signalling

View full text Add to dashboard Cite

Lysine residues are subject to a multitude of reversible post-translational modifications, including acetylation and SUMOylation. In the heart, enhancement of lysine acetylation or SUMOylation using histone deacetylase (HDAC) inhibitors or SUMO-1 gene transfer, respectively, has been shown to be cardioprotective. Here, we addressed whether there is crosstalk between lysine acetylation and SUMOylation in the heart. Treatment of cardiomyocytes and cardiac fibroblasts with pharmacological inhibitors of HDAC catalytic activity robustly increased conjugation of SUMO-1, but not SUMO-2/3, to several high molecular weight proteins in both cell types. Use of a battery of selective HDAC inhibitors and short hairpin RNAs demonstrated that HDAC2, which is a class I HDAC, is the primary HDAC isoform that controls cardiac protein SUMOylation. HDAC inhibitors stimulated protein SUMOylation in the absence of de novo gene transcription or protein synthesis, revealing a post-translational mechanism of HDAC inhibitor action. HDAC inhibition did not suppress the activity of de-SUMOylating enzymes, suggesting that increased protein SUMOylation in HDAC inhibitor-treated cells is due to stimulation of SUMO-1 conjugation rather than blockade of SUMO-1 cleavage. Consistent with this, multiple components of the SUMO conjugation machinery were capable of being acetylated in vitro. These findings reveal a novel role for reversible lysine acetylation in the control of SUMOylation in the heart, and suggest that cardioprotective actions of HDAC inhibitors are in part due to stimulation of protein SUMO-1-ylation in myocytes and fibroblasts.

show abstract

Section: Discussionmentioning

confidence: 99%

Class I HDAC inhibition stimulates cardiac protein SUMOylation through a post-translational mechanism

Blakeslee

Wysoczynski

Fritz

et al. 2014

Cellular Signalling

View full text Add to dashboard Cite

show abstract

“…There is extensive evidence that regulation of histone post-translational modifications contribute to the etiology and progression of ischemic damage in the brain [25][26][27][28].…”

Section: Histone Modificationsmentioning

confidence: 99%

Ischemic Preconditioning Alters the Epigenetic Profile of the Brain from Ischemic Intolerance to Ischemic Tolerance

et al. 2013

View full text Add to dashboard Cite

Ischemic preconditioning is an innate neuroprotective mechanism in which a sub-injurious ischemic exposure increases the brain's ability to withstand a subsequent, normally injurious ischemic insult. Part of ischemic preconditioning neuroprotection stems from an epigenetic reprogramming of the brain to a phenotype of ischemic tolerance, which results in a gene expression profile different from that observed in the non-injured and ischemia-injured brains. Such neuroprotective reprograming, activated by ischemic preconditioning, requires specific changes in DNA accessibility coordinated with activation of transcriptional activator and repressor proteins, which allows for expression of specific neuroprotective proteins despite a general repression of gene expression. In this review we examine the effects of injurious ischemia and ischemic preconditioning on the regulation of DNA methylation, histone post-translational modifications, and non-coding RNA expression. There is increasing interest in the role of epigenetics in disease pathobiology, and whether and how pharmacological manipulation of epigenetic processes may allow for ischemic neuroprotection. Therefore, a better understanding of the epigenomic determinants underlying the modulation of gene expression that lead to ischemic tolerance or cell death offers the promise of novel neuroprotective therapies that target global reprograming of genomic activity versus individual cellular signaling pathways.

show abstract

“…45 Because histone deacetylase inhibitors have recently surged as potent agents to blunt ischemia/reperfusion injury, it would be interesting to study how much of that is attributed by the derepression of MEF2-depedent transcription. 46,47 In conclusion, here we show the immediate transcriptional responses to myocardial ischemia in a clinically relevant large animal model of AMI. For the first time, GRO-Seq was used to detect acute transcriptional changes in response to ischemia in vivo.…”

Section: Discussionmentioning

confidence: 51%

Genome-Wide Dynamics of Nascent Noncoding RNA Transcription in Porcine Heart After Myocardial Infarction

Halonen

Liu

Turunen

et al. 2017

Circ Cardiovasc Genet

View full text Add to dashboard Cite

Background— Microarrays and RNA sequencing are widely used to profile transcriptome remodeling during myocardial ischemia. However, the steady-state RNA analysis lacks in sensitivity to detect all noncoding RNA species and does not provide separation between transcriptional and post-transcriptional regulations. Here, we provide the first comprehensive analysis of nascent RNA profiles of mRNAs, primary micro-RNAs, long noncoding RNAs, and enhancer RNAs in a large animal model of acute infarction. Methods and Results— Acute infarction was induced by cardiac catheterization of domestic swine. Nuclei isolated from healthy, border zone, and ischemic regions of the affected heart were subjected to global run-on sequencing. Global run-on sequencing analysis indicated that half of affected genes are regulated at the level of transcriptional pausing. A gradient of induction of inflammatory mediators and repression of peroxisome proliferator-activated receptor signaling and oxidative phosphorylation was detected when moving from healthy toward infarcted area. In addition, we interrogated the transcriptional regulation of primary micro-RNAs and provide evidence that several arrhythmia-related target genes exhibit repression at post-transcriptional level. We identified 450 long noncoding RNAs differently regulated by ischemia, including novel conserved long noncoding RNAs expressed in antisense orientation to myocardial transcription factors GATA-binding protein 4, GATA-binding protein 6, and Krüppel-like factor 6. Finally, characterization of enhancers exhibiting differential expression of enhancer RNAs pointed a central role for Krüppel-like factor, MEF2C, ETS, NFY, ATF, E2F2, and NRF1 transcription factors in determining transcriptional responses to ischemia. Conclusions— Global run-on sequencing allowed us to follow the gradient of gene expression occurring in the ischemic heart and identify novel noncoding RNAs regulated by oxygen deprivation. These findings highlight potential new targets for diagnosis and treatment of myocardial ischemia.

show abstract

Potential Roles of HDAC Inhibitors in Mitigating Ischemia-induced Brain Damage and Facilitating Endogenous Regeneration and Recovery

Cited by 75 publications

References 186 publications

Class I HDAC inhibition stimulates cardiac protein SUMOylation through a post-translational mechanism

Class I HDAC inhibition stimulates cardiac protein SUMOylation through a post-translational mechanism

Ischemic Preconditioning Alters the Epigenetic Profile of the Brain from Ischemic Intolerance to Ischemic Tolerance

Genome-Wide Dynamics of Nascent Noncoding RNA Transcription in Porcine Heart After Myocardial Infarction

Contact Info

Product

Resources

About