Associate editor: P. Molenaar
Posttranslational modifications of histone deacetylases: Implications for cardiovascular diseases

https://doi.org/10.1016/j.pharmthera.2014.02.012Get rights and content

Abstract

Posttranslational modification (PTM) is a term that implies dynamic modification of proteins after their translation. PTM is involved not only in homeostasis but also in pathologic conditions related to diverse diseases. Histone deacetylases (HDACs), which are known as transcriptional regulators, are one example of posttranslational modifiers with diverse roles in human pathophysiology, including cardiovascular diseases. In experimental models, HDAC inhibitors are beneficial in supraventricular arrhythmia, myocardial infarction, cardiac remodeling, hypertension, and fibrosis. In addition, HDACs are closely related to other vascular diseases such as neointima formation, atherosclerosis, and vascular calcification. Currently, HDACs are classified into four different classes. The class IIa HDACs work as transcriptional regulators mainly by direct association with other transcription factors to their target binding elements in a phosphorylation-dependent manner. Class I HDACs, by contrast, have much greater enzymatic activity than the class II HDACs and target various non-histone proteins as well as the histone-core complex. Class I HDACs undergo PTMs such as phosphorylation, sumoylation, and S-nitrosylation. Considering the growing evidence for the role of HDACs in cardiovascular diseases, the PTMs of the HDACs themselves as well as HDAC-mediated PTM of their targets should be considered for future potential therapeutic targets. In this review, we discuss 1) the roles of each HDAC in specific cardiovascular diseases and 2) the PTM of HDACs, 3) and the implications of such modifications for cardiovascular diseases.

Introduction

Since the 1970s, cardiovascular disease (CVD) has been a leading cause of death throughout the world (Hunter & Reddy, 2013). Although great efforts have been made by physicians, researchers, and even primary care practitioners to reduce the mortality due to CVD, the disease is still a major cause of death in developed countries. In large part because of unbalanced, high-fat diets, the median age of patients with CVD has been decreasing (McGill et al., 2008). “Cardiovascular disease” is a term indicating medical problems in the heart, the blood vessels, or both. Sometimes CVD indicates “heart disease” in a limited sense; usually, however, vascular problems in the brain or kidney or other peripheral arterial disease is also included. The most common CVDs are hypertension and atherosclerosis (Ross, 1999). Even in healthy individuals, aging followed by morphological and physiological changes affects cardiovascular structures and function, which subsequently leads to a high risk of CVD. Therefore, risk-factor-reducing efforts such as consuming a balanced healthy diet, getting adequate amounts of exercise, increasing lean body mass, and stopping smoking are strongly recommended to reduce the development of CVD (McGill et al., 2008). Besides a preventive approach, therapeutic interventions to halt disease progress or to recover a healthy state are necessary as well, and such interventions require a fundamental understanding of disease development and progress. Considering that most CVD-related pathologic events are caused by malfunction of normal proteins, PTMs that might result in those abnormal behaviors should be extensively studied. Thus, understanding the PTMs associated with CVD may offer opportunities for the development of ideal therapeutics with maximal efficacy and minimal unwanted effects.

Proteins are not stable but are dynamically modified by other proteins, such as kinases, acetyltransferases, methyltransferases, ubiquitinylases, and carboxylases. These changes are finely balanced by opposing enzymes such as phosphatases, deacetylases, demethylases, deubiquitinylases, and decarboxylases. These dynamic changes are called PTMs and are closely linked to diverse cellular functions and human diseases. For example, when ligands occupy their binding sites in receptors, receptor tyrosine kinases phosphorylate target molecules and an extracellular signal is delivered to cytoplasmic or nuclear targets (Hubbard & Till, 2000). Phosphorylation is an essential modification in the regulation of enzyme activation (Stambolic and Woodgett, 1994, Dimmeler et al., 1999), DNA-binding capacity (Beg et al., 1993), formation of complexes (Maudsley et al., 2000), and cell cycle regulation (Serrano et al., 1993).

Besides phosphorylation, ubiquitination is an important modification that has been intensively investigated recently. Ubiquitin is a small protein with a molecular mass of just 8.5 kDa. It has 7 lysine residues in its structure. Ubiquitination indicates the covalent binding of ubiquitin to a substrate. This process generally involves binding of glycine 76 at the C-terminus of ubiquitin to a lysine of the substrate. Polyubiquitination refers to additional ligation of ubiquitin to another ubiquitin that has already been conjugated with a protein, which implies that ubiquitin works as a substrate for further ubiquitination. Two lysines of ubiquitin are involved in polyubiquitination: Lys-48 and Lys-63. Lys-48-linked polyubiquitination is associated with protein degradation and recycling by proteolysis (Glickman & Ciechanover, 2002), whereas Lys-63-linked polyubiquitination is atypical and is involved in other processes such as inflammation, DNA repair, and endocytic trafficking (Miranda & Sorkin, 2007). In contrast to polyubiquitination, monoubiquitination, which is also frequently observed, has quite different biological functions. Although monoubiquitination is sometimes regarded as a beginning step of polyubiquitination, most monoubiquitination solely affects cellular events such as endocytosis, trafficking, and signal transduction such as phosphorylation (Miranda & Sorkin, 2007). Small ubiquitin-like modifier (SUMO) proteins are analogous to ubiquitin, and the characteristics of SUMO modification, which is termed sumoylation, resemble those of monoubiquitination (Melchior, 2000).

Likewise, protein acetylation, an alternate well-known PTM, has a unique biological function. Perhaps one of the best documented targets of acetylation involves histone H3 and H4 proteins; acetylation of the histone tail is closely associated with transcriptional activation. The positive charge of the histone core is neutralized by adding an acetyl moiety, which thereby loosens the tight interaction between the negative charge of the phosphate group in DNA and the histone tail (de Ruijter et al., 2003). The nucleosome is then opened to the transcriptional machinery, which initiates gene expression. Non-histone proteins are also susceptible to acetylation, which affects enzyme activity (Santos-Rosa et al., 2003), protein–protein interaction (Levy et al., 2004), DNA recruitment (Gu & Roeder, 1997), and transcriptional activity (Evans et al., 2007).

It is noteworthy that each PTM can affect other modifications; indeed, we can easily find multiple modifications at different residues in a single molecule or even at a single residue, which seems like “competition” between the various modifications. For example, acetylation, methylation, and ubiquitination commonly occur at a lysine residue, and these modifications sometimes regulate the target protein function in a competitive manner. Histone H3 Lys-9 is a target site for both acetylation and methylation, and trimethylated Lys-9 is found in constitutively repressed genes (Barski et al., 2007). In contrast, acetylation on this residue activates gene expression (Koch et al., 2007). Following the removal of the methyl group by specific demethylases, histone acetyltransferase (HAT) enzyme acetylates H3 Lys-9. By contrast, after the acetyl moiety is removed by histone deacetylase (HDAC), the remaining unmodified lysine residue is subject to mono-, di-, and tri-methyl modification (Guillemette et al., 2011). Indeed, growing evidence suggests that HDAC works in conjunction with histone methyltransferase (Wysocka et al., 2003). Similarly, acetylation increases protein stability by competition with polyubiquitination (Li et al., 2002). Furthermore, PTM-associated PTMs such as acetylation-dependent phosphorylation (Park et al., 2003), phosphorylation-dependent acetylation (Corre et al., 2009), or phosphorylation-dependent ubiquitination (Koepp et al., 2001, Lin et al., 2002) are also reported.

Protein acetylation is finely regulated by two different groups of enzymes: HATs and HDACs. At least 18 different HDACs in mammals have been discovered, which are categorized into four classes. HDAC1, 2, 3, and 8 are members of the class I HDACs; HDAC4, 5, 6, 7, 9, and 10 are class II HDACs; the sirtuin family members, Sirt1, Sirt2, Sirt3, Sirt4, Sirt5, Sirt6, and Sirt7, are class III HDACs; and HDAC11 is the only class IV HDAC. Class I, II, and IV HDACs contain and require zinc ion for their enzyme activity (Minucci & Pelicci, 2006); however, class III HDACs are NAD+-dependent (Blander & Guarente, 2004). Like the HATs, HDACs also have non-histone substrates (Chen et al., 2002, Hubbert et al., 2002, Ito et al., 2002, Watamoto et al., 2003, Ito et al., 2006). Thus, it has been suggested that lysine deacetylase, or KDAC, would be more appropriate nomenclature because histone is not the only substrate and these non-histone targets have more diverse biological functions than transcriptional regulation (Choudhary et al., 2009). In the present review, we discuss the roles and PTMs of the class I and class II HDACs and their mechanisms of regulation in association with CVD.

Section snippets

Histone deacetylases

The criterion applied to divide the class I and class II HDACs is based on the homology of each HDAC to yeast HDACs (Blander & Guarente, 2004). Class II HDACs consist of 1) a large N terminus regulatory region, 2) an HDAC domain, and 3) a short tail in the C terminus. Class II HDACs form a huge complex by interaction with distinct corepressors or epigenetic regulators and thereby suppress the gene expression of downstream targets (McKinsey et al., 2000a). The class I HDACs, however, do not have

Non-histone targets of histone acetyltransferase and histone deacetylase in association with cardiovascular disease

Adult heart is a typical organ whose cell cycle is arrested. Proliferation ability, however, is transiently observed, although rapidly abolished in the perinatal period. Very interestingly, rebirth of the fetal gene programs that are arrested in adult heart has drawn much interest in regard to adult CVD. This process is closely related to development during the embryonic period. Thus, the role of acetyl-protein and its modifiers in fetal development may have applications in adult cardiac

Possible limitations of histone deacetylase modifiers in therapeutic application

Early tissue distribution studies that used serial analysis of gene expression (SAGE) profiles suggested that class IIa HDACs are expressed in limited organs such as the muscles, brain, or bone, whereas class I HDACs exist ubiquitously. Indeed, class I HDACs are expressed in most cells. Thus, one may question the specificity and adverse effects of HDACi when they are used for therapeutics. According to HDAC2 whole-body deletion study, however, it should be noted that the expression profile of

Conclusions and future perspectives

In this review, we summarize 1) the role of HDACs in CVD, 2) the PTMs of HDACs in cardiovascular diseases, and 3) the implications of the PTM of the HDACs. According to HDACi studies, HDAC inhibition has a beneficial outcome in supraventricular tachyarrhythmia, MI, cardiac remodeling including eccentric hypertrophy, hypertension, cardiac fibrosis, and muscular dystrophy. However, it may worsen neointimal proliferation, atherosclerosis, vascular calcifications, and COPD. Actually, thrombus

Conflict of interest statement

The authors declare that there are no conflicts of interests.

Acknowledgments

The authors are grateful for critical comments by Dr. Jonathan A. Epstein of the University of Pennsylvania. This study was supported by a National Research Foundation of Korea grant funded by the Korean government (MEST, #2012-0005602), by the National Research Foundation of Korea grant (MRC, 2011–0030132) funded by the Korea government (MSIP), and by a grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A121561).

References (157)

  • E.J. Fitzgerald O'Connor et al.

    Histone deacetylase 2 is upregulated in normal and keloid scars

    J Invest Dermatol

    (2012)
  • H. Geng et al.

    HDAC4 protein regulates HIF1alpha protein lysine acetylation and cancer cell response to hypoxia

    J Biol Chem

    (2011)
  • M.A. Glozak et al.

    Acetylation and deacetylation of non-histone proteins

    Gene

    (2005)
  • J.W. Gordon et al.

    Protein kinase A-regulated assembly of a MEF2{middle dot}HDAC4 repressor complex controls c-Jun expression in vascular smooth muscle cells

    J Biol Chem

    (2009)
  • W. Gu et al.

    Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain

    Cell

    (1997)
  • C.H. Ha et al.

    Protein kinase D-dependent phosphorylation and nuclear export of histone deacetylase 5 mediates vascular endothelial growth factor-induced gene expression and angiogenesis

    J Biol Chem

    (2008)
  • I.F. Harrison et al.

    Epigenetic targeting of histone deacetylase: therapeutic potential in Parkinson's disease?

    Pharmacol Ther

    (2013)
  • P. Jones et al.

    A series of novel, potent, and selective histone deacetylase inhibitors

    Bioorg Med Chem Lett

    (2006)
  • P. Jones et al.

    Probing the elusive catalytic activity of vertebrate class IIa histone deacetylases

    Bioorg Med Chem Lett

    (2008)
  • H.Y. Kao et al.

    Isolation and characterization of mammalian HDAC10, a novel histone deacetylase

    J Biol Chem

    (2002)
  • T. Kawamura et al.

    Acetylation of GATA-4 is involved in the differentiation of embryonic stem cells into cardiac myocytes

    J Biol Chem

    (2005)
  • H.J. Kee et al.

    Kruppel-like factor 4 mediates histone deacetylase inhibitor-induced prevention of cardiac hypertrophy

    J Mol Cell Cardiol

    (2009)
  • H.J. Kee et al.

    Trichostatin A prevents neointimal hyperplasia via activation of Kruppel like factor 4

    Vascul Pharmacol

    (2011)
  • X. Kong et al.

    HDAC2 deacetylates class II transactivator and suppresses its activity in macrophages and smooth muscle cells

    J Mol Cell Cardiol

    (2009)
  • M. Li et al.

    Acetylation of p53 inhibits its ubiquitination by Mdm2

    J Biol Chem

    (2002)
  • F. Liu et al.

    Histone-deacetylase inhibition reverses atrial arrhythmia inducibility and fibrosis in cardiac hypertrophy independent of angiotensin

    J Mol Cell Cardiol

    (2008)
  • S. Maudsley et al.

    The beta(2)-adrenergic receptor mediates extracellular signal-regulated kinase activation via assembly of a multi-receptor complex with the epidermal growth factor receptor

    J Biol Chem

    (2000)
  • F. Meng et al.

    All-trans retinoic acid increases KLF4 acetylation by inducing HDAC2 phosphorylation and its dissociation from KLF4 in vascular smooth muscle cells

    Biochem Biophys Res Commun

    (2009)
  • T. Azechi et al.

    Trichostatin A, an HDAC class I/II inhibitor, promotes pi-induced vascular calcification via up-regulation of the expression of alkaline phosphatase

    J Atheroscler Thromb

    (2013)
  • A.A. Beg et al.

    Tumor necrosis factor and interleukin-1 lead to phosphorylation and loss of I kappa B alpha: a mechanism for NF-kappa B activation

    Mol Cell Biol

    (1993)
  • G. Blander et al.

    The Sir2 family of protein deacetylases

    Annu Rev Biochem

    (2004)
  • H.J. Bogaard et al.

    Suppression of histone deacetylases worsens right ventricular dysfunction after pulmonary artery banding in rats

    Am J Respir Crit Care Med

    (2011)
  • J. Bossuyt et al.

    Ca2+/calmodulin-dependent protein kinase IIdelta and protein kinase D overexpression reinforce the histone deacetylase 5 redistribution in heart failure

    Circ Res

    (2008)
  • A. Brandl et al.

    Dynamically regulated sumoylation of HDAC2 controls p53 deacetylation and restricts apoptosis following genotoxic stress

    J Mol Cell Biol

    (2012)
  • E.W. Bush et al.

    Targeting histone deacetylases for heart failure

    Expert Opin Ther Targets

    (2009)
  • M.A. Cavasin et al.

    Selective class I histone deacetylase inhibition suppresses hypoxia-induced cardiopulmonary remodeling through an antiproliferative mechanism

    Circ Res

    (2012)
  • S. Chang et al.

    Histone deacetylases 5 and 9 govern responsiveness of the heart to a subset of stress signals and play redundant roles in heart development

    Mol Cell Biol

    (2004)
  • L.F. Chen et al.

    Acetylation of RelA at discrete sites regulates distinct nuclear functions of NF-kappaB

    EMBO J

    (2002)
  • Y.K. Cho et al.

    Sodium valproate, a histone deacetylase inhibitor, but not captopril, prevents right ventricular hypertrophy in rats

    Circ J

    (2010)
  • J.H. Choi et al.

    Trichostatin A exacerbates atherosclerosis in low density lipoprotein receptor-deficient mice

    Arterioscler Thromb Vasc Biol

    (2005)
  • C. Choudhary et al.

    Lysine acetylation targets protein complexes and co-regulates major cellular functions

    Science

    (2009)
  • C. Colussi et al.

    HDAC2 blockade by nitric oxide and histone deacetylase inhibitors reveals a common target in Duchenne muscular dystrophy treatment

    Proc Natl Acad Sci U S A

    (2008)
  • M.P. Czubryt et al.

    Regulation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) and mitochondrial function by MEF2 and HDAC5

    Proc Natl Acad Sci U S A

    (2003)
  • A.J. de Ruijter et al.

    Histone deacetylases (HDACs): characterization of the classical HDAC family

    Biochem J

    (2003)
  • C.F. Deroanne et al.

    Histone deacetylases inhibitors as anti-angiogenic agents altering vascular endothelial growth factor signaling

    Oncogene

    (2002)
  • S. Dimmeler et al.

    Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation

    Nature

    (1999)
  • M. Duvic et al.

    Vorinostat: a new oral histone deacetylase inhibitor approved for cutaneous T-cell lymphoma

    Expert Opin Investig Drugs

    (2007)
  • G.H. Eom et al.

    Casein kinase-2alpha1 induces hypertrophic response by phosphorylation of histone deacetylase 2 S394 and its activation in the heart

    Circulation

    (2011)
  • G.H. Eom et al.

    Regulation of Acetylation of Histone Deacetylase 2 by p300/CBP–Associated Factor/Histone Deacetylase 5 in the Development of Cardiac Hypertrophy

    Circ Res

    (2014)
  • H.M. Findeisen et al.

    Epigenetic regulation of vascular smooth muscle cell proliferation and neointima formation by histone deacetylase inhibition

    Arterioscler Thromb Vasc Biol

    (2011)
  • Cited by (0)

    View full text