Pharmacological inhibition of the acetyltransferase Tip60 mitigates myocardial infarction injury. Dis Model Mech 2023 May 01;16(5)
Date
11/08/2022Pubmed ID
36341679Pubmed Central ID
PMC9672930DOI
10.1242/dmm.049786Scopus ID
2-s2.0-85141362492 (requires institutional sign-in at Scopus site) 5 CitationsAbstract
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.
Author List
Wang X, Wan TC, Kulik KR, Lauth A, Smith BC, Lough JW, Auchampach JAAuthors
John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinBrian C. Smith PhD Associate Professor in the Biochemistry department at Medical College of Wisconsin
Tina C. Wan PhD Research Scientist II in the Pediatrics department at Medical College of Wisconsin
Xinrui Wang PhD Assistant Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsApoptosis
Histone Acetyltransferases
Histones
Mice
Myocardial Infarction
Myocytes, Cardiac
