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

Wang, Xinrui; Wan, Tina C.; Lauth, Amelia; Purdy, Alexandra L; Kulik, Katherine; Patterson, Michaela; Lough, John; Auchampach, John A.

doi:10.1016/j.yjmcc.2021.09.012

Cited by 15 publications

(28 citation statements)

References 57 publications

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“…2). Similar to gap junction dysmorphology we recently described in Tip60-depleted hearts [14], this indicated that the pattern of Connexin-43 staining was disrupted in hearts of the majority of mice treated with TH1834.…”

Section: Left Column)supporting

confidence: 84%

“…To address the role of Tip60 in the ischemic heart, wherein it is robustly expressed [12, 13], we conditionally disrupted the Kat5 gene encoding Tip60 in CMs of adult mice three days after induction of MI produced by permanent left coronary artery ligation. As recently reported [14], we found that Cre-mediated depletion of Tip60 markedly preserved cardiac function for up to 28 days post-MI and limited the extent of scarring by ~30%. These findings were accompanied by reduced CM apoptosis, diminished induction of DDR markers in CMs, and activation of the CM cell-cycle.…”

Section: Introductionsupporting

confidence: 87%

“…Similar trends toward cell-cycle activation were observed in non-CMs at day 28 post-MI, ie, hearts in the TH1834-treated group show more Ki67- and BrdU-positive non-CMs, respectively in the border and remote zones (right panels in Fig. 5); although this phenomenon, which is also observed in infarcted hearts following disruption of the Kat5 gene, is unexplained, we previously speculated that it represents a CM-based paracrine effect, and/or compensated changes resultant from MI [14].…”

Section: Resultsmentioning

confidence: 99%

“…As shown in the experimental timeline (Fig. 1C), which is similar to the strategy we previously employed to genetically target Kat5 [14], we assessed the effect of daily intraperitoneal administration of 10 mg/kg TH1834, beginning on the third day after myocardial infarction (MI), for 14 consecutive days, ending on the sixteenth day post-MI. During this period, cardiac function was monitored by echocardiography at the indicated intervals (Fig.…”

Section: Th1834 Experimental Strategymentioning

confidence: 99%

“…These findings were accompanied by reduced CM apoptosis, diminished induction of DDR markers in CMs, and activation of the CM cell-cycle. These findings demonstrated that genetic depletion of Tip60 markedly protected against the damaging effects of MI, which might be explained by enhanced CM proliferation and survival [14].…”

Section: Introductionmentioning

confidence: 99%

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Mitigation of Injury from Myocardial Infarction by TH1834, an Inhibitor of the Acetyltransferase Tip60

Wang

Wan

Kulik

et al. 2021

Preprint

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It is estimated that up to one billion cardiomyocytes (CMs) can be lost during myocardial infarction (MI), which results in contractile dysfunction, adverse ventricular remodeling, and systolic heart failure. Pharmacologic strategies that target factors having both pro-apoptotic and anti-proliferative functions in CMs may be useful for the treatment of ischemic heart disease. One such multifunctional candidate for drug targeting is the acetyltransferase Tip60, which is a member of the MYST family of acetyltransferases known to acetylate both histone and non-histone protein targets that have been shown in cultured cancer cells to promote apoptosis and to initiate the DNA damage response (DDR) thereby limiting cellular expansion. Using a murine model, we recently published findings demonstrating that CM-specific disruption of the Kat5 gene encoding Tip60 markedly protected against the damaging effects of 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 two weeks of a 4-week timeline resulted in improved systolic function assessed by echocardiography, reduced apoptosis and scarring, reduced expression of markers of the DDR, and increased activation of the CM cell-cycle. Our results support that idea that drugs that inhibit the acetyltransferase activity of Tip60 may be useful agents for the treatment of ischemic heart disease.

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Section: Left Column)supporting

confidence: 84%

Section: Introductionsupporting

confidence: 87%

Section: Resultsmentioning

confidence: 99%

Section: Th1834 Experimental Strategymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Mitigation of Injury from Myocardial Infarction by TH1834, an Inhibitor of the Acetyltransferase Tip60

Wang

Wan

Kulik

et al. 2021

Preprint

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RGS7 balances acetylation/de-acetylation of p65 to control chemotherapy-dependent cardiac inflammation

Basak,

Das,

Mahata

et al. 2023

Cell. Mol. Life Sci.

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Targeting cardiomyocyte cell cycle regulation in heart failure

Zhu,

Yuan,

Krishnan

2024

Basic Res Cardiol

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Heart failure continues to be a significant global health concern, causing substantial morbidity and mortality. The limited ability of the adult heart to regenerate has posed challenges in finding effective treatments for cardiac pathologies. While various medications and surgical interventions have been used to improve cardiac function, they are not able to address the extensive loss of functioning cardiomyocytes that occurs during cardiac injury. As a result, there is growing interest in understanding how the cell cycle is regulated and exploring the potential for stimulating cardiomyocyte proliferation as a means of promoting heart regeneration. This review aims to provide an overview of current knowledge on cell cycle regulation and mechanisms underlying cardiomyocyte proliferation in cases of heart failure, while also highlighting established and novel therapeutic strategies targeting this area for treatment purposes.

show abstract

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

Cited by 15 publications

References 57 publications

Mitigation of Injury from Myocardial Infarction by TH1834, an Inhibitor of the Acetyltransferase Tip60

Mitigation of Injury from Myocardial Infarction by TH1834, an Inhibitor of the Acetyltransferase Tip60

RGS7 balances acetylation/de-acetylation of p65 to control chemotherapy-dependent cardiac inflammation

Targeting cardiomyocyte cell cycle regulation in heart failure

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