Protective Effect of Geranylgeranylacetone via Enhancement of HSPB8 Induction in Desmin-Related Cardiomyopathy

Sanbe, Atsushi; Daicho, Takuya; Mizutani, Reiko; Endo, Toshiya; Miyauchi, Noriko; Yamauchi, Junji; Tanonaka, Kouichi; Glabe, Charles G.; Tanoue, Akito

doi:10.1371/journal.pone.0005351

Cited by 93 publications

(140 citation statements)

References 34 publications

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“…3B, Bottom). We directly confirmed this by collecting soluble and insoluble cellular fractions and measuring CryAB in the insoluble fraction; this is a well-documented method for determining insoluble aggregate content (16,42,43). The insoluble fraction derived from cells overexpressing HDAC6 showed elevated CryAB levels compared with controls ( Fig.…”

Section: Inhibiting Hdac6 Reduces Aggregate Formation In Cardiomyocytessupporting

confidence: 53%

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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Section: Inhibiting Hdac6 Reduces Aggregate Formation In Cardiomyocytessupporting

confidence: 53%

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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“…The first compound is geranyl geranylacetone (GGA), a compound that induces HSP expression, and which is marketed as an anti ulcer agent in Japan, with no reports of serious adverse reactions 194 . In the experi mental setting, GGA enables cardio myocytes to cope with proteotoxic stress by attenuating damage to the sarcomeres, refolding dam aged proteins, and assisting in the degradation of damaged proteins by inducing the expression of genes encoding HSPs, especially small HSPs 26,39,195 . Similarly, GGA induction of HSPB1 and HSPB8 expression attenu ates the progression of HF in the Cryab R120G transgenic mouse model of desmin related cardiomyopathy by reducing aggregate formation, resulting in the attenu ation of fibrosis and improvement of heart function and overall survival 195 .…”

Section: Pharmacological Modulation Of Pqcmentioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

140

126

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The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

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“…To distinguish the transgenic products from endogenous protein, a FLAG epitope was introduced at the N terminus of CryAB R120G. An HA epitope was introduced at the N terminus of HSPB8 as described previously (12,13).…”

Section: Methodsmentioning

confidence: 99%

“…The cellular toxicity of the recombinant HSPB8, HSPB8 K141N, CryAB, and CryAB R120G protein in HEK293T cells as well as cardiomyocytes was determined using a 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Recombinant proteins were added to give a final concentration of 0.4 mg/ml in serumfree Dulbecco's modified Eagle's medium and incubated for 12 h. After incubation, MTT assays were performed as described previously (12,13).…”

Section: Methodsmentioning

confidence: 99%

“…To study the structure-function relationship of a single missense mutation of HSPB8 in vivo, cardiac-specific TG mice expressing HSPB8 K141N as well as wild-type HSPB8 TG mice as controls were generated using tetracycline-controlled transcriptional activator (tTA) and the attenuated myosin heavy chain system (11,12). The phenotype of HSPB8 K141N TG mice is an accumulation of aggregates containing HSPB8, causing slightly impaired cardiac function, mild ventricular hypertrophy, and apical cardiac fibrosis with cardiac mitochondrial dysfunction at approximately 6 months of age.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Phenotype of Cardiomyopathy in Cardiac-specific Heat Shock Protein B8 K141N Transgenic Mouse

Sanbe

Marunouchi

Abe

et al. 2013

Journal of Biological Chemistry

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Background: A lys141Asn (K141N) missense mutation in heat shock protein (HSP) B8 causes distal hereditary motor neuropathy (HMN). Results: HSPB8 K141N transgenic mice exhibited mild hypertrophy and apical fibrosis as well as slightly reduced cardiac function. Conclusion: A single point mutation of HSPB8, such as K141N, can cause cardiac disease. Significance: The cardiomyopathy phenotype was observed in cardiac-specific HSPB8 K141N transgenic mice.

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Protective Effect of Geranylgeranylacetone via Enhancement of HSPB8 Induction in Desmin-Related Cardiomyopathy

Cited by 93 publications

References 34 publications

Tubulin hyperacetylation is adaptive in cardiac proteotoxicity by promoting autophagy

Tubulin hyperacetylation is adaptive in cardiac proteotoxicity by promoting autophagy

Proteostasis in cardiac health and disease

Phenotype of Cardiomyopathy in Cardiac-specific Heat Shock Protein B8 K141N Transgenic Mouse

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