Epigenetics, an inheritable phenomenon, which influences the expression of gene without altering the DNA sequence, offers a new perspective on the pathogenesis of hepatocellular carcinoma (HCC). Nonalcoholic steatohepatitis (NASH) is projected to account for a significant share of HCC incidence due to the growing prevalence of various metabolic disorders. One of the major molecular mechanisms involved in epigenetic regulation, post-translational histone modification seems to coordinate various aspects of NASH which will further progress to HCC. Mounting evidence suggests that the orchestrated events of cellular and nuclear changes during apoptosis can be regulated by histone modifications. This review focuses on the current advances in the study of acetylation-/methylation-mediated histone modification in apoptosis and the implication of these epigenetic regulations in HCC. The reversibility of epigenetic alterations and the agents that can target these alterations offers novel therapeutic approaches and strategies for drug development. Further molecular mechanistic studies are required to enhance information governing these epigenetic modulators, which will facilitate the design of more effective diagnosis and treatment options.

At concentrations found in human after ingestion of 1-2 cups of green tea, Epicatechin-3-gallate (ECG) modulates Na/K-ATPase conformation and activity. Akin to ouabain, an archetypal Na/K-ATPase ligand of the cardiotonic steroids (CTS) family, ECG also activates PKCɛ translocation and increases the force of contraction of the rat heart. This study evaluated whether, like ouabain, ECG also modulates Na/K-ATPase/Src receptor function and triggers pre- and post-conditioning against ischemia/reperfusion (I/R) injury. In vitro, ECG activated the purified Na/K-ATPase/Src complex. In Langendorff-perfused rat hearts, sub-micromolar concentrations of ECG administered either before or after ischemia reduced infarct size by more than 40%, decreased lactate dehydrogenase release, and improved the recovery of cardiac function. ECG protection was blocked by PKCɛ inhibition and attenuated by mitochondrial KATP channel inhibition. In a unique mammalian cell system with depleted Na/K-ATPase α1 expression, ECG-induced PKCɛ activation persisted but protection against I/R was blunted. Taken together, these results reveal a Na/K-ATPase- and PKCɛ-dependent mechanism of protection by ECG that is also distinct from the mechanism of action of ouabain. These ECG properties likely contribute to the positive impact of green tea consumption on cardiovascular health and warrant further investigation into the role of cardiac Na/K-ATPase signaling in the cardioprotective effect of green tea consumption. SIGNIFICANCE STATEMENT Consumption of green tea, the richest dietary source of ECG, is associated with a reduced risk of cardiac mortality. Anti-oxidant effects of ECG and other tea polyphenols are well known, but reported for concentrations well above dietary levels. Therefore, the mechanism underlying the cardioprotective effect of green tea remains incompletely understood. This study provides experimental evidence that ECG concentrations commonly detected in human after consumption of a cup of tea trigger Na/K-ATPase/Src receptor in a cell-free system, activate a CTS-like signaling pathway, and provide PKCε-dependent protection against ischemia/reperfusion injury in rat hearts. Mechanistic studies in mammalian cells with targeted Na/K-ATPase depletion revealed that although Na/K-ATPase does not mediate ECG-induced PKCɛ activation, it is required for ECG-induced protection against ischemia/reperfusion injury.

The first reports of cardiac Na/K-ATPase signaling, published 20 years ago, have opened several major fields of investigations into the cardioprotective action of low/subinotropic concentrations of cardiotonic steroids (CTS). This review focuses on the protective cardiac Na/K-ATPase-mediated signaling triggered by low concentrations of ouabain and other CTS, in the context of the enduring debate over the use of CTS in the ischemic heart. Indeed, as basic and clinical research continues to support effectiveness and feasibility of conditioning interventions against ischemia/reperfusion injury in acute myocardial infarction (AMI), the mechanistic information available to date suggests that unique features of CTS-based conditioning could be highly suitable, alone /or as a combinatory approach.

Cardiac glycosides (CG) are traditionally known as positive cardiac inotropes that inhibit Na+/K+‐ATPase‐dependent ion transport. CG also trigger‐specific signaling pathways through the cardiac Na+/K+‐ATPase, with beneficial effects in ischemia/reperfusion (I/R) injury (e.g., ouabain preconditioning, known as OPC) and hypertrophy. Our current understanding of hypersensitivity to CG and subsequent toxicity in the ischemic heart is mostly based on specific I/R‐induced alterations of the Na+/K+‐ATPase enzymatic function and has remained incomplete. The primary goal of this study was to investigate and compare the impact of I/R on Na+/K+‐ATPase enzymatic and signaling functions. Second, we assessed the impact of OPC on both functions. Langendorff‐perfused rat hearts were exposed to 30 min of ischemia and 30 min of reperfusion. At the inotropic concentration of 50 μmol/L, ouabain increased ERK and Akt phosphorylation in control hearts. In I/R hearts, this concentration did not induced positive inotropy and failed to induce Akt or ERK phosphorylation. The inotropic response to dobutamine as well as insulin signaling persisted, suggesting specific alterations of Na+/K+‐ATPase. Indeed, Na+/K+‐ATPase protein expression was intact, but the enzyme activity was decreased by 60% and the enzymatic function of the isoform with high affinity for ouabain was abolished following I/R. Strikingly, OPC prevented all I/R‐induced alterations of the receptor. Further studies are needed to reveal the respective roles of I/R‐induced modulations of Na+/K+‐ATPase enzymatic and signaling functions in cardiomyocyte death.