Histone deacetylase inhibition reduces myocardial ischemia‐reperfusion injury in mice

Granger, Anne; Abdullah, Ibrahim; Huebner, Faith; Stout, Andrea L.; Wang, Tao; Huebner, Thomas; Epstein, Jonathan A.; Gruber, Peter J.

doi:10.1096/fj.08-108548

Cited by 249 publications

(226 citation statements)

References 46 publications

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“…For example, diverse pathologies such as Huntington's disease and cardiac I/R injury show proteotoxic phenotypes and display protein hypoacetylation (25,40,41), suggesting HDAC hyperactivity. We analyzed the acetylation profile of our proteotoxic disease model, in which CryAB R120G is expressed in cardiomyocytes of TG mice, resulting in the development of heart disease between 3 and 7 mo (9,14).…”

Section: Resultsmentioning

confidence: 99%

“…These data clearly show that HDAC6 promotes aggregate formation in cardiomyocytes, and inhibiting HDAC6-mediated tubulin deacetylation inhibits aggregate accumulation. HDAC inhibitor therapies have been and are being explored due to their apparent effectiveness in certain proteotoxic disease models (25,40,44). We subsequently treated the cultures with SAHA, an FDA-approved hydroxamic acid-based pan-HDAC inhibitor that inhibits class IIb HDAC activity.…”

Section: Inhibiting Hdac6 Reduces Aggregate Formation In Cardiomyocytesmentioning

confidence: 99%

“…heart disease (23)(24)(25)(26)(27). HDACs are enzymes that remove acetyl groups from lysine residues on histones and cytoplasmic proteins, but can also affect gene expression, protein function, and cell signaling (28).…”

mentioning

confidence: 99%

“…HDACs are enzymes that remove acetyl groups from lysine residues on histones and cytoplasmic proteins, but can also affect gene expression, protein function, and cell signaling (28). In the context of cardiac stress, HDAC activity is increased (25,29) and HDAC inhibitors can reduce hypertrophy induced by pressure overload (29,30). Several HDACs, including HDAC6, have been implicated in promoting autophagy and, as such, HDAC inhibitors may also impact on these processes.…”

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confidence: 99%

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Tubulin hyperacetylation is adaptive in cardiac proteotoxicity by promoting autophagy

McLendon

Ferguson

Osińska

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

106

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Proteinopathy causes cardiac disease, remodeling, and heart failure but the pathological mechanisms remain obscure. Mutated αB-crystallin (CryAB R120G ), when expressed only in cardiomyocytes in transgenic (TG) mice, causes desmin-related cardiomyopathy, a protein conformational disorder. The disease is characterized by the accumulation of toxic misfolded protein species that present as perinuclear aggregates known as aggresomes. Previously, we have used the CryAB R120G model to determine the underlying processes that result in these pathologic accumulations and to explore potential therapeutic windows that might be used to decrease proteotoxicity. We noted that total ventricular protein is hypoacetylated while hyperacetylation of α-tubulin, a substrate of histone deacetylase 6 (HDAC6) occurs. HDAC6 has critical roles in protein trafficking and autophagy, but its function in the heart is obscure. Here, we test the hypothesis that tubulin acetylation is an adaptive process in cardiomyocytes. By modulating HDAC6 levels and/or activity genetically and pharmacologically, we determined the effects of tubulin acetylation on aggregate formation in CryAB R120G cardiomyocytes. Increasing HDAC6 accelerated aggregate formation, whereas siRNA-mediated knockdown or pharmacological inhibition ameliorated the process. HDAC inhibition in vivo induced tubulin hyperacetylation in CryAB R120G TG hearts, which prevented aggregate formation and significantly improved cardiac function. HDAC6 inhibition also increased autophagic flux in cardiomyocytes, and increased autophagy in the diseased heart correlated with increased tubulin acetylation, suggesting that autophagy induction might underlie the observed cardioprotection. Taken together, our data suggest a mechanistic link between tubulin hyperacetylation and autophagy induction and points to HDAC6 as a viable therapeutic target in cardiovascular disease.P roteotoxicity is an important yet understudied mechanism in cardiac pathobiology (1), as maintaining tight control of protein homeostasis is critical for proper cell function. This is especially important in the unique context of the heart, as it is under constant mechanical and oxidative stress, and cardiomyocytes appear to be largely postmitotic soon after birth and are unable to readily regenerate (2, 3). Cellular stress events, including normal physiologic stimuli, can lead to altered cardiomyocyte function if the pathways of protein quality control (PQC) are compromised. Pathological cardiac stress, including pressure overload-induced hypertrophy and ischemia-reperfusion (I/R) injury, can alter protein degradation pathways (4-6). Our laboratory has developed a model of cardiac proteotoxicity based upon transgenically mediated cardiomyocyte expression of a mutated αB-crystallin (CryAB R120G ), which causes desminrelated cardiomyopathy in humans (7-9).CryAB is a molecular chaperone for desmin, an intermediate filament protein expressed in myocytes. Desmin is a crucial cardiomyocyte protein with vital signaling and structural ro...

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Section: Resultsmentioning

confidence: 99%

Section: Inhibiting Hdac6 Reduces Aggregate Formation In Cardiomyocytesmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Tubulin hyperacetylation is adaptive in cardiac proteotoxicity by promoting autophagy

McLendon

Ferguson

Osińska

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

106

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“…Class I and class IIa HDAC inhibitors have shown promise in ameliorating the effects of adverse tissue remodeling post-MI. Several comprehensive in vivo studies have shown that pan-HDAC inhibitors such as suberoylanilide acid, TSA, and valproic acid not only reduce infarct scar area but also improve cardiac function after an MI (22,49,72,76).…”

Section: Class II Hdacs In Cardiovascular Diseasementioning

confidence: 99%

A class of their own: exploring the nondeacetylase roles of class IIa HDACs in cardiovascular disease

Wright

Menick

2016

American Journal of Physiology-Heart and Circulatory Physiology

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Histone deacetylases (HDACs) play integral roles in many cardiovascular biological processes ranging from transcriptional and translational regulation to protein stabilization and localization. There are 18 known HDACs categorized into 4 classes that can differ on the basis of substrate targets, subcellular localization, and regulatory binding partners. HDACs are classically known for their ability to remove acetyl groups from histone and nonhistone proteins that have lysine residues. However, despite their nomenclature and classical functions, discoveries from many research groups over the past decade have suggested that nondeacetylase roles exist for class IIa HDACs. This is not surprising given that class IIa HDACs have, for example, relatively poor deacetylase capabilities and are often shuttled in and out of nuclei upon specific pathological and nonpathological cardiac events. This review aims to consolidate and elucidate putative nondeacetylase roles for class IIa HDACs and, where possible, highlight studies that provide evidence for their noncanonical roles, especially in the context of cardiovascular maladies. There has been great interest recently in exploring the pharmacological regulators of HDACs for use in therapeutic interventions for treating cardiovascular diseases and inflammation. Thus it is of interest to earnestly consider nonenzymatic and or nondeacetylase roles of HDACs that might be key in potentiating or abrogating pathologies. These noncanonical HDAC functions may possibly yield new mechanisms and targets for drug discovery.

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Stress response factors as hub‐regulators of microRNA biogenesis: implication to the diseased heart

Gurianova

Stroy

Ciccocioppo

et al. 2015

Cell Biochemistry & Function

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MicroRNAs (miRNAs) are important regulators of heart function and then an intriguing therapeutic target for plenty of diseases. The problem raised is that many data in this area are contradictory, thus limiting the use of miRNA-based therapy. The goal of this review is to describe the hub-mechanisms regulating the biogenesis and function of miRNAs, which could help in clarifying some contradictions in the miRNA world. With this scope, we analyse an array of factors, including several known agents of stress response, mediators of epigenetic changes, regulators of alternative splicing, RNA editing, protein synthesis and folding and proteolytic systems. All these factors are important in cardiovascular function and most of them regulate miRNA biogenesis, but their influence on miRNAs was shown for non-cardiac cells or some specific cardiac pathologies. Finally, we consider that studying the stress response factors, which are upstream regulators of miRNA biogenesis, in the diseased heart could help in (1) explaining some contradictions concerning miRNAs in heart pathology, (2) making the role of miRNAs in pathogenesis of cardiovascular disease more clear, and therefore, (3) getting powerful targets for its molecular therapy.

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Histone deacetylase inhibition reduces myocardial ischemia‐reperfusion injury in mice

Cited by 249 publications

References 46 publications

Tubulin hyperacetylation is adaptive in cardiac proteotoxicity by promoting autophagy

Tubulin hyperacetylation is adaptive in cardiac proteotoxicity by promoting autophagy

A class of their own: exploring the nondeacetylase roles of class IIa HDACs in cardiovascular disease

Stress response factors as hub‐regulators of microRNA biogenesis: implication to the diseased heart

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