Histone Deacetylase 3 (HDAC3)-dependent Reversible Lysine Acetylation of Cardiac Myosin Heavy Chain Isoforms Modulates Their Enzymatic and Motor Activity

Samant, Sadhana; Pillai, Vinodkumar B.; Sundaresan, Nagalingam R.; Shroff, Sanjeev G.; Gupta, Mahesh P.

doi:10.1074/jbc.m115.653048

Cited by 34 publications

(23 citation statements)

References 33 publications

(46 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Acetyl-proteomics studies have demonstrated extensive acetylation of proteins that comprise cardiac myofibrils (31). In vitro experiments showed that acetylation of α- and β-MyHC increased the actin-sliding velocity of both myosin isoforms, which would be predicted to speed the exponential phase of relaxation, and HDAC3 was implicated as the MyHC deacetylase (32). However, HDAC3-mediated deacetylation of MyHC is unlikely to account for our observations, because we failed to see a significant amount of HDAC3 co-purifying with myofibrils.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism

et al. 2018

View full text Add to dashboard Cite

There are no approved drugs for the treatment of heart failure with preserved ejection fraction (HFpEF), which is characterized by left ventricular (LV) diastolic dysfunction. We demonstrate that ITF2357 (givinostat), a clinical-stage inhibitor of histone deacetylase (HDAC) catalytic activity, is efficacious in two distinct murine models of diastolic dysfunction with preserved EF. ITF2357 blocked LV diastolic dysfunction due to hypertension in Dahl salt-sensitive (DSS) rats and suppressed aging-induced diastolic dysfunction in normotensive mice. HDAC inhibitor–mediated efficacy was not due to lowering blood pressure or inhibiting cellular and molecular events commonly associated with diastolic dysfunction, including cardiac fibrosis, cardiac hypertrophy, or changes in cardiac titin and myosin isoform expression. Instead, ex vivo studies revealed impairment of cardiac myofibril relaxation as a previously unrecognized, myocyte-autonomous mechanism for diastolic dysfunction, which can be ameliorated by HDAC inhibition. Translating these findings to humans, cardiac myofibrils from patients with diastolic dysfunction and preserved EF also exhibited compromised relaxation. These data suggest that agents such as HDAC inhibitors, which potentiate cardiac myofibril relaxation, hold promise for the treatment of HFpEF in humans.

show abstract

Section: Discussionmentioning

confidence: 99%

Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Eventually, non-histone protein acetylation was also discovered, starting with p53 [17] and expanding to non-histone proteins throughout the cell [18]. As the field has expanded, it has come to be appreciated that the acetylation state of non-histone proteins and enzymes can dramatically affect characteristics of the acetylated proteins, including protein stability [19,20], enzymatic activity [21,22], DNA binding [23], and intracellular localization [24]. These changes in protein characteristics can have a profound effect on cellular processes, including those determining the fate of cells subjected to injury.…”

Section: Introductionmentioning

confidence: 99%

HDAC1 localizes to the mitochondria of cardiac myocytes and contributes to early cardiac reperfusion injury

Herr

Baarine

Aune

et al. 2018

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

Rationale Recent evidence indicates that histone deacetylase enzymes (HDACs) contribute to ischemia re-perfusion (I/R) injury, and pan-HDAC inhibitors have been shown to be cardioprotective when administered either before an ischemic insult or during reperfusion. We have shown previously that selective inhibition of class I HDACs provides superior cardioprotection when compared to pan-HDAC inhibition in a pretreatment model, but selective class I HDAC inhibition has not been tested during reperfusion, and specific targets of class I HDACs in I/R injury have not been identified. Objective We hypothesized that selective inhibition of class I HDACs with the drug MS-275 (entinostat) during reperfusion would improve recovery from I/R injury in the first hour of reperfusion. Methods and results Hearts from male Sprague-Dawley rats were subjected to ex vivo I/R injury ± MS-275 class I HDAC inhibition during reperfusion alone. MS-275 significantly attenuated I/R injury, as indicated by improved LV function and tissue viability at the end of reperfusion. Unexpectedly, we observed that HDAC1 is present in the mitochondria of cardiac myocytes, but not fibroblasts or endothelial cells. We then designed mitochondria-restricted and mitochondria-excluded HDAC inhibitors, and tested both in our ex vivo I/R model. The selective inhibition of mitochondrial HDAC1 attenuated I/R injury to the same extent as MS-275, whereas the mitochondrial-excluded inhibitor did not. Further assays demonstrated that these effects are attributable to a decrease in SDHA activity and subsequent metabolic ROS production in reperfusion. Conclusions We demonstrate for the first time that HDAC1 is present within the mitochondria of cardiac myocytes, and mitochondrial HDAC1 contributes significantly to I/R injury within the first hour of reperfusion.

show abstract

“…For instance, Ferguson et al found that class I HDAC inhibition repressed cardiac hypertrophy induced by several pathological insults in vitro via inhibition of ERK1/2 by Dual Specificity Phosphatase 5 (DUSP5) (18). Furthermore, HDAC3 was reportedly involved in different aspects of heart pathologic change, including heart failure (19), hypertrophy (20) and abnormal energy metabolism (21), but so far no information is available for its role in DCM.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway

et al. 2017

View full text Add to dashboard Cite

Inhibition of total histone deacetylases (HDACs) was phenomenally associated with the prevention of diabetic cardiomyopathy (DCM). However, which specific HDAC plays the key role in DCM remains unclear. The present study was designed to determine whether DCM can be prevented by specific inhibition of HDAC3 and to elucidate the mechanisms by which inhibition of HDAC3 prevent DCM. Type 1 diabetes OVE26 and age-matched wild-type mice were given the selective HDAC3 inhibitor RGFP966 or vehicle for 3 months. These mice were then sacrificed immediately or 3 months later for cardiac function and pathological examination. HDAC3 activity was significantly increased in the heart of diabetic mice. Administration of RGFP966 significantly prevented DCM, as evidenced by improved diabetes-induced cardiac dysfunction, hypertrophy and fibrosis, along with diminished cardiac oxidative stress, inflammation, and insulin resistance, not only in the mice sacrificed immediately or 3 months later following the three-month treatment. Furthermore, phosphorylated extracellular signal-regulated kinases (ERK) 1/2, a well-known initiator of cardiac hypertrophy, was significantly increased, while dual specificity phosphatase 5 (DUSP5), an ERK1/2 nuclear phosphatase, was substantially decreased in diabetic hearts. Both of these changes were prevented by RGFP966. Chromatin immunoprecipitation assay showed that HDAC3 inhibition elevated histone H3 acetylation on the DUSP5 gene promoter at both two-time points. These findings suggest that diabetes-activated HDAC3 inhibits DUSP5 expression through deacetylating histone H3 on the primer region of DUSP5 gene, leading to the derepression of ERK1/2 and the initiation of DCM. This study indicates the potential application of HDAC3 inhibitor for the prevention of DCM.

show abstract

Histone Deacetylase 3 (HDAC3)-dependent Reversible Lysine Acetylation of Cardiac Myosin Heavy Chain Isoforms Modulates Their Enzymatic and Motor Activity

Cited by 34 publications

References 33 publications

Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism

Histone deacetylase activity governs diastolic dysfunction through a nongenomic mechanism

HDAC1 localizes to the mitochondria of cardiac myocytes and contributes to early cardiac reperfusion injury

Inhibition of HDAC3 prevents diabetic cardiomyopathy in OVE26 mice via epigenetic regulation of DUSP5-ERK1/2 pathway

Contact Info

Product

Resources

About