Evidence of Histone H2A.Z Deacetylation and Cardiomyocyte Dedifferentiation in Infarcted/Tip60-depleted Hearts.

Myocardial infarction (MI) in the human heart causes death of billions of cardiomyocytes (CMs), resulting in cardiac dysfunction that is incompatible with life or lifestyle. In order to re-muscularize injured myocardium, replacement CMs must be generated via renewed proliferation of surviving CMs. Approaches designed to induce proliferation of CMs after injury have been insufficient. Toward this end, we are targeting the Tip60 acetyltransferase, based on the rationale that its pleiotropic functions conspire to block the CM cell-cycle at several checkpoints. We previously reported that genetic depletion of Tip60 in a mouse model after MI reduces scarring, retains cardiac function, and activates the CM cell-cycle, although it is unclear whether this culminates in the generation of daughter CMs. For pre-existing CMs in the adult heart to resume proliferation, it is becoming widely accepted that they must first dedifferentiate, a process highlighted by loss of maturity, epithelial to mesenchymal transitioning (EMT), and reversion from fatty acid oxidation to glycolytic metabolism, accompanied by softening of the myocardial extracellular matrix. Findings in hematopoietic stem cells, and more recently in neural progenitor cells, have shown that Tip60 induces and maintains the differentiated state via site-specific acetylation of the histone variant H2A.Z. Here, we report that genetic depletion of Tip60 from naïve or infarcted hearts results in the near-complete absence of acetylated H2A.Z in CM nuclei, and that this is accordingly accompanied by altered gene expressions indicative of EMT induction, ECM softening, decreased fatty acid oxidation, and depressed expression of genes that regulate the TCA cycle. These findings, combined with our previous work, support the notion that because Tip60 has multiple targets that combinatorially maintain the differentiated state and inhibit proliferation, its transient therapeutic targeting to ameliorate the effects of cardiac injury should be considered.

Pharmacological inhibition of the acetyltransferase Tip60 mitigates myocardial infarction injury.

Pharmacologic strategies that target factors with both pro-apoptotic and anti-proliferative functions in cardiomyocytes (CMs) may be useful for the treatment of ischemic heart disease. One such multifunctional candidate for drug targeting is the acetyltransferase Tip60, which is known to acetylate both histone and non-histone protein targets that have been shown in cancer cells to promote apoptosis and to initiate the DNA damage response, thereby limiting cellular expansion. Using a murine model, we recently published findings demonstrating that CM-specific disruption of the Kat5 gene encoding Tip60 markedly protects against the damaging effects of myocardial infarction (MI). In the experiments described here, in lieu of genetic targeting, we administered TH1834, an experimental drug designed to specifically inhibit the acetyltransferase domain of Tip60. We report that, similar to the effect of disrupting the Kat5 gene, daily systemic administration of TH1834 beginning 3 days after induction of MI and continuing for 2 weeks of a 4-week timeline resulted in improved systolic function, reduced apoptosis and scarring, and increased activation of the CM cell cycle, effects accompanied by reduced expression of genes that promote apoptosis and inhibit the cell cycle and reduced levels of CMs exhibiting phosphorylated Atm. These results support the possibility that drugs that inhibit the acetyltransferase activity of Tip60 may be useful agents for the treatment of ischemic heart disease.

Conditional depletion of the acetyltransferase Tip60 protects against the damaging effects of myocardial infarction.

Injury from myocardial infarction (MI) and consequent post-MI remodeling is accompanied by massive loss of cardiomyocytes (CM), a cell type critical for contractile function that is for all practical purposes non-regenerable due to its profound state of proliferative senescence. Identification of factors that limit CM survival and/or constrain CM renewal provides potential therapeutic targets. Tip60, a pan-acetyltransferase encoded by the Kat5 gene, has been reported to activate apoptosis as well as multiple anti-proliferative pathways in non-cardiac cells; however, its role in CMs, wherein it is abundantly expressed, remains unknown. Here, using mice containing floxed Kat5 alleles and a tamoxifen-activated Myh6-MerCreMer recombinase transgene, we report that conditional depletion of Tip60 in CMs three days after MI induced by permanent coronary artery ligation greatly improves functional recovery for up to 28 days. This is accompanied by diminished scarring, activation of cell-cycle transit markers in CMs within the infarct border and remote zones, reduced expression of cell-cycle inhibitors pAtm and p27, and reduced apoptosis in the remote regions. These findings implicate Tip60 as a novel, multifactorial target for limiting the damaging effects of ischemic heart disease.

History of US Presidential Assaults on Modern Environmental Health Protection.

The Trump administration has undertaken an assault on the Environmental Protection Agency (EPA), an agency critical to environmental health. This assault has precedents in the administrations of Ronald Reagan and George W. Bush. The early Reagan administration (1981-1983) launched an overt attack on the EPA, combining deregulation with budget and staff cuts, whereas the George W. Bush administration (2001-2008) adopted a subtler approach, undermining science-based policy. The current administration combines both these strategies and operates in a political context more favorable to its designs on the EPA. The Republican Party has shifted right and now controls the executive branch and both chambers of Congress. Wealthy donors, think tanks, and fossil fuel and chemical industries have become more influential in pushing deregulation. Among the public, political polarization has increased, the environment has become a partisan issue, and science and the mainstream media are distrusted. For these reasons, the effects of today's ongoing regulatory delays, rollbacks, and staff cuts may well surpass those of the administrations of Reagan and Bush, whose impacts on environmental health were considerable.