Histone Deacetylase Inhibitors: A Novel Strategy for Neuroprotection and Cardioprotection Following Ischemia/Reperfusion Injury

Abstract

Ischemia/reperfusion injury is a complex molecular cascade that causes deleterious cellular damage and organ dysfunction. Stroke, sudden cardiac arrest, and acute myocardial infarction are the most common causes of ischemia/reperfusion injury without effective pharmacologic therapies. Existing preclinical evidence suggests that histone deacetylase inhibitors may be an efficacious, affordable, and clinically feasible therapy that can improve neurologic and cardiac outcomes following ischemia/reperfusion injury. In this review, we discuss the pathophysiology and epigenetic modulations of ischemia/reperfusion injury and focus on the neuroprotective and cardioprotective effects of histone deacetylase inhibitors. We also summarize the protective effects of histone deacetylase inhibitors for other vital organs and highlight the key research priorities for their successful translation to the bedside.

Keywords: cardiac arrest; epigenetics; histone deacetylase inhibitors; myocardial infarction; stroke.

Figure 1. Mechanisms of ischemia‐reperfusion injury. Ischemia induces anerobic glycolysis, intracellular acidosis, and ion pump dysfunction.

The subsequent calcium influx combined with prolonged ischemia results in cellular necrosis. On reperfusion and restoration of physiologic pH, reactive oxygen species (ROS) generation and intracellular calcium trigger mitochondrial permeability transition pore (MPTP) opening and induce further intracellular calcium overload, proinflammatory cascades, and apoptosis.

Figure 2. Epigenetic effects of histone deacetylase (HDAC) inhibition in the brain.

Chromatins are composed of negatively charged DNA wrapped around nucleosomes, each of which consists of 8 positively charged histones (2 sets of H2A, H2B, H3, and H4). HDAC inhibitors (HDACi) inhibit HDACs, resulting in the removal of positive charges on histone H3 and H4 through acetylation. The subsequent unwinding of DNA from the nucleosomes exposes genes to RNA polymerase for transcription. The relevant genes regulated by HDACi for neuroprotection after ischemia/reperfusion injury are highlighted. ARC indicates apoptosis repressor with caspase recruitment domain; BDNF, brain‐derived neurotrophic factor; Foxm1, forkhead box M1; GSK3B, glycogen synthase kinase 3β; HSP70, heat shock protein 70; IL, interleukin; iNOS, inducible nitric oxide synthase; mTOR, mechanistic target of rapamycin kinase; NEUROD1, neuronal differentiation 1; PAI‐1, plasminogen activator inhibitor 1; t‐PA, tissue‐type plasminogen activator.