Systematic review and meta-analysis of experimental studies evaluating the organ protective effects of histone deacetylase inhibitors.pdf (2.74 MB)
Systematic review and meta-analysis of experimental studies evaluating the organ protective effects of histone deacetylase inhibitors.
journal contributionposted on 2019-09-03, 11:10 authored by SI Yusoff, M Roman, FY Lai, B Eagle-Hemming, GJ Murphy, T Kumar, M Wozniak
The clinical efficacy of organ protection interventions are limited by the redundancy of cellular activation mechanisms. Interventions that target epigenetic mechanisms overcome this by eliciting genome wide changes in transcription and signaling. We aimed to review preclinical studies evaluating the organ protection effects of histone deacetylase inhibitors (HDACi) with a view to informing the design of early phase clinical trials. A systematic literature search was performed. Methodological quality was assessed against prespecified criteria. The primary outcome was mortality, with secondary outcomes assessing mechanisms. Prespecified analyses evaluated the effects of likely moderators on heterogeneity. The analysis included 101 experimental studies in rodents (n = 92) and swine (n = 9), exposed to diverse injuries, including: ischemia (n = 72), infection (n = 7), and trauma (n = 22). There were a total of 448 comparisons due to the evaluation of multiple independent interventions within single studies. Sodium valproate (VPA) was the most commonly evaluated HDACi (50 studies, 203 comparisons). All of the studies were judged to have significant methodological limitations. HDACi reduced mortality in experimental models of organ injury (risk ratio = 0.52, 95% confidence interval 0.40-0.68, p < 0.001) without heterogeneity. HDACi administration resulted in myocardial, brain and kidney protection across diverse species and injuries that was attributable to increases in prosurvival cell signaling, and reductions in inflammation and programmed cell death. Heterogeneity in the analyses of secondary outcomes was explained by differences in species, type of injury, HDACi class (Class I better), drug (trichostatin better), and time of administration (at least 6 hours prior to injury better). These findings highlight a potential novel application for HDACi in clinical settings characterized by acute organ injury.
Professor Murphy reports grants from British Heart Foundation during the conduct of the study and grants from British Heart Foundation, grants from National Institute for Health Research, grants from Zimmer Biomet, and personal fees from Thrasos Inc, outside the submitted work. The other authors declare no conflicts of interest. G.J.M., T.K., M.W., and F.L. (CH/12/1/29419) and S.Y. (RG/13/6/29947) are supported by the British Heart Foundation Grant. M.R. is an NIHR Clinical Lecturer. No funding sources were used in support of this work.
CitationTranslational Research, 2019, 205, pp. 1-16
Author affiliation/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Department of Cardiovascular Sciences
- VoR (Version of Record)