Inhibition of histone deacetylases triggers pharmacologic preconditioning effects against myocardial ischemic injury

Zhao, Ting C.; Cheng, Guangmao; Zhang, Ling X.; Tseng, Yi‐Tang; Padbury, Jamés F.

doi:10.1016/j.cardiores.2007.08.010

Cited by 133 publications

(121 citation statements)

References 47 publications

(71 reference statements)

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“…HDAC4 is expressed in the heart, stem cells, the endothelium, and vascular smooth muscle cells (1,4,12,19,21). Cardioprotective effects of HDAC inhibition against injury have been well identified (45,47,48). Our recent observation demonstrates that HDAC inhibition enhanced myocardial repair in vivo through stimulation of endogenous regeneration (46), which is in line with our observation that HDAC inhibition facilitated the embryonic stem cells' differentiation into cardiac lineages and enhanced resistance to oxidant stress (4).…”

supporting

confidence: 86%

Specific inhibition of HDAC4 in cardiac progenitor cells enhances myocardial repairs

Zhang

DeNicola

Qin

et al. 2014

American Journal of Physiology-Cell Physiology

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We have recently shown that in vivo inhibition of histone deacetylase (HDAC) stimulates endogenous myocardial regeneration in infarcted hearts (Zhang L et al. J Pharmacol Exp Ther 341: 285-293, 2012). Furthermore, our observation demonstrates that HDAC inhibition promotes cardiogenesis, which is associated with HDAC4 reduction. However, it remains unknown as to whether specific inhibition of HDAC4 modulates cardiac stem cells (CSCs) to facilitate myocardial repair and to preserve cardiac performance. c-kit ϩ CSCs were isolated from adult mouse hearts and were transfected with HDAC4 siRNA to knockdown HDAC4 of c-kit ϩ CSCs. The transfection of HDAC4 siRNA caused a marked reduction of HDAC4 mRNA and proteins in c-kit ϩ CSCs. Mouse myocardial infarction (MI) was created to assess the effect of HDAC4 inhibition in c-kit ϩ CSCs on myocardial regeneration in vivo when cells were introduced into MI hearts. Transplantation of HDAC4 siRNA-treated c-kit ϩ CSCs into MI hearts improved ventricular function, attenuated ventricular remodeling, and promoted CSC-derived regeneration and neovascularization. Furthermore, Ki67 and BrdU positively proliferative myocytes increased in MI hearts receiving HDAC4 siRNA-treated c-kit ϩ CSCs compared with MI hearts engrafted with control siRNA-treated c-kit ϩ CSCs. In addition, compared with MI hearts engrafted with control adenoviral GFPinfected c-kit ϩ CSCs, MI hearts receiving adenoviral HDAC4-infected c-kit ϩ CSCs exhibited attenuated cardiac functional recovery, CSC-derived regeneration, and neovascularization, which was accompanied with adverse ventricular remodeling and decrease in Ki67 and BrdU positively proliferative myocytes. HDAC4 inhibition facilitated c-kit ϩ CSCs into the differentiation into cardiac lineage commitments in vitro, while HDAC4 overexpression attenuated c-kit ϩ CSC-derived cardiogenesis. Our results indicate that HDAC4 inhibition promotes CSC-derived cardiac regeneration and improves the restoration of cardiac function.heart; HDAC4; regeneration; myocardial infarction; stem cells IT HAS NOW BEEN RECOGNIZED that adult hearts harbor distinct populations of cardiac progenitors (2,25,26,34), which have the potential to differentiate into cardiomyocytes, endothelia, and vascular smooth muscle cells. Furthermore, several studies have shown that these cardiac progenitor cells are capable of differentiating into cardiac tissue and improving cardiac function after a myocardial injury. Exponential advances in stem cell and regenerative biology are beginning to foster a transition toward therapeutic goals for cardiac regenerative medicine (8,14,15,33). However, poor cell viability, proliferation, and inefficient differentiation following transplantation have limited the reparative capacity of these cells in vivo (26,29,39). Thus molecular intervention strategies to enhance cardiac stem cell (CSC) proliferation and survival hold dramatic consequences for enhancing myogenesis and will empower therapeutically relevant implementation of myocardial regeneration. It was repor...

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supporting

confidence: 86%

Specific inhibition of HDAC4 in cardiac progenitor cells enhances myocardial repairs

Zhang

DeNicola

Qin

et al. 2014

American Journal of Physiology-Cell Physiology

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“…Administration of sodium butyrate 24 h prior to and then again 4 h prior to permanent MCAO reduced infarct size by approximately 50 % at 24 h when compared with vehicle-treated controls [33]. This finding suggests that HDAC inhibition may be able to precondition the brain against ischemic damage, as has been demonstrated in the heart using the HDAC inhibitor trichostatin A [35].…”

Section: Acetylationmentioning

confidence: 60%

Ischemic Preconditioning Alters the Epigenetic Profile of the Brain from Ischemic Intolerance to Ischemic Tolerance

et al. 2013

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Ischemic preconditioning is an innate neuroprotective mechanism in which a sub-injurious ischemic exposure increases the brain's ability to withstand a subsequent, normally injurious ischemic insult. Part of ischemic preconditioning neuroprotection stems from an epigenetic reprogramming of the brain to a phenotype of ischemic tolerance, which results in a gene expression profile different from that observed in the non-injured and ischemia-injured brains. Such neuroprotective reprograming, activated by ischemic preconditioning, requires specific changes in DNA accessibility coordinated with activation of transcriptional activator and repressor proteins, which allows for expression of specific neuroprotective proteins despite a general repression of gene expression. In this review we examine the effects of injurious ischemia and ischemic preconditioning on the regulation of DNA methylation, histone post-translational modifications, and non-coding RNA expression. There is increasing interest in the role of epigenetics in disease pathobiology, and whether and how pharmacological manipulation of epigenetic processes may allow for ischemic neuroprotection. Therefore, a better understanding of the epigenomic determinants underlying the modulation of gene expression that lead to ischemic tolerance or cell death offers the promise of novel neuroprotective therapies that target global reprograming of genomic activity versus individual cellular signaling pathways.

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“…This highlights the need to better understand the pathogenic mechanisms and here we investigate the potential role of aberrant protein acetylation. This appears to be a common feature in proteinopathies (25,29,41,56) and, importantly, drugs to inhibit overactive deacetylation are available and in clinical use.…”

Section: Discussionmentioning

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.…”

mentioning

confidence: 99%

Tubulin hyperacetylation is adaptive in cardiac proteotoxicity by promoting autophagy

McLendon

Ferguson

Osińska

et al. 2014

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

101

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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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Inhibition of histone deacetylases triggers pharmacologic preconditioning effects against myocardial ischemic injury

Abstract: These results suggest that inhibition of HDACs triggers pharmacologic preconditioning to protect the ischemic heart, which involves p38 activation.

Cited by 133 publications

References 47 publications

Specific inhibition of HDAC4 in cardiac progenitor cells enhances myocardial repairs

Specific inhibition of HDAC4 in cardiac progenitor cells enhances myocardial repairs

Ischemic Preconditioning Alters the Epigenetic Profile of the Brain from Ischemic Intolerance to Ischemic Tolerance

Tubulin hyperacetylation is adaptive in cardiac proteotoxicity by promoting autophagy

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