Novel Histone Deacetylase Inhibitor Modulates Cardiac Peroxisome Proliferator-Activated Receptors and Inflammatory Cytokines in Heart Failure

Lkhagva, Baigalmaa; Lin, Yung Kuo; Kao, Yu Hsun; Chazo, Tze Fan; Chung, Cheng Chih; Chen, Shih Ann; Chen, Yi Jen

doi:10.1159/000438864

Cited by 32 publications

(16 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TNF-a significantly increased HDAC activity with elevated HDAC1 messenger RNA and protein expressions in synovial tissues and fibroblasts [26]. In addition, isoproterenol-induced HF was associated with increased expressions of Class I HDACs (HDAC-1, -2, and -3), HDACIIa (HDAC4), and HDACIIb (HDAC6), which suggests that TNF-a may induce cardiac dysfunction through the actions of HDACs [27]. Increased HDAC1 activity by TNF-a was hypothesized to result in nuclear factor (NF)-kBdependent inflammatory gene expression [28,29].…”

Section: Discussionmentioning

confidence: 99%

Activation of Class I histone deacetylases contributes to mitochondrial dysfunction in cardiomyocytes with altered complex activities

et al. 2018

Self Cite

View full text Add to dashboard Cite

Histone deacetylases (HDACs) play vital roles in the pathophysiology of heart failure, which is associated with mitochondrial dysfunction. Tumor necrosis factor-α (TNF-α) contributes to the genesis of heart failure and impairs mitochondria. This study evaluated the role of HDACs in TNF-α-induced mitochondrial dysfunction and investigated their therapeutic potential and underlying mechanisms. We measured mitochondrial oxygen consumption rate (OCR) and ATP production using Seahorse XF24 extracellular flux analyzer and bioluminescent assay in control and TNF-α (10 ng/ml, 24 h)-treated HL-1 cells with or without HDAC inhibition. TNF-α increased Class I and II (but not Class IIa) HDAC activities (assessed by Luminescent) with enhanced expressions of Class I (HDAC1, HDAC2, HDAC3, and HDAC8) but not Class IIb HDAC (HDAC6 and HDAC10) proteins in HL-1 cells. TNF-α induced mitochondrial dysfunction with impaired basal, ATP-linked, and maximal respiration, decreased cellular ATP synthesis, and increased mitochondrial superoxide production (measured by MitoSOX red fluorescence), which were rescued by inhibiting HDACs with MPT0E014 (1 μM, a Class I and IIb inhibitor), or MS-275 (1 μM, a Class I inhibitor). MPT0E014 reduced TNF-α-decreased complex I and II enzyme (but not III or IV) activities (by enzyme activity microplate assays). Our results suggest that Class I HDAC actions contribute to TNF-α-induced mitochondrial dysfunction in cardiomyocytes with altered complex I and II enzyme regulation. HDAC inhibition improves dysfunctional mitochondrial bioenergetics with attenuation of TNF-α-induced oxidative stress, suggesting the therapeutic potential of HDAC inhibition in cardiac dysfunction.

show abstract

Section: Discussionmentioning

confidence: 99%

Activation of Class I histone deacetylases contributes to mitochondrial dysfunction in cardiomyocytes with altered complex activities

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…Classically HDACs deacetylate nucleosome histones and alter the electrostatic properties of chromatin in a manner that represses gene expression (30, 31). Inhibition of HDACs using small molecules such as butyrate, VPA or trichostatin A exerts multiple cardioprotective effects, such as the anti-hypertrophy (32, 33), anti-fibrosis (34, 35), anti-oxidative stress (36), anti-inflammation (37, 38), and anti-apoptosis (39) under non-diabetic conditions, and also anti-DCM (14, 15). Although HDACs are the promising therapeutic target for multiple cardiovascular diseases, the diversity of HDAC isoforms constrain the practice.…”

Section: Discussionmentioning

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

“…At 12 weeks of age, the rats were grouped into three groups of eight rats each, including control, HFD + low-dose STZ-induced T2DM and MPT0E014-treated HFD + low-dose STZ-induced T2DM groups. MPT0E014 [a pan-HDAC inhibitor (15); 50 mg/kg in 50% polyethylene glycol 400 and 0.25% carboxymethyl cellulose (22)], or a vehicle (1 ml/kg of 50% polyethylene glycol 400 and 0.25% carboxymethyl cellulose) was given once daily for 7 days by oral gavage in the studied rats. The rats were sacrificed with an intraperitoneal injection of sodium pentobarbital (100 mg/kg) at 13 weeks of age.…”

Section: Methodsmentioning

confidence: 99%

Histone deacetylase inhibition of cardiac autophagy in rats on a high‑fat diet with low‑dose streptozotocin-induced type 2 diabetes mellitus

et al. 2017

View full text Add to dashboard Cite

Autophagy serves a role in preserving cellular homeostasis. Diabetes mellitus (DM) impairs cardiac autophagy and is associated with an accumulation of cytotoxic proteins that may provoke apoptosis and damage cardiomyocytes. Histone deacetylase (HDAC) inhibitors attenuate cardiac fibrosis and inflammation, and improve cardiomyopathy resulting from DM. However, the effect of HDAC inhibition on autophagy in DM cardiomyopathy has not been investigated. The purpose of the present study was to evaluate whether HDAC inhibition modulates cardiac autophagy and to investigate the potential mechanisms in type 2 DM (T2DM) hearts. Electrocardiography was used to evaluate cardiac function and western blotting was used to evaluate protein expression in autophagy, the serine/threonine protein kinase mTOR (mTOR) signaling pathway, poly adenosine diphosphate ribose polymerase 1 (PARP1), insulin signaling, advanced glycosylation end product‑specific receptor (RAGE), and proinflammatory cytokines in control rats and in rats treated with a high‑fat diet (60% fat) and low‑dose streptozotocin (35 mg/kg) in order to induce T2DM, with or without an HDAC inhibitor (MPT0E014; 50 mg/kg/rat daily for 7 days). Compared with the control rats, T2DM and T2DM rats treated with MPT0E014 exhibited elevated blood glucose levels and similar body weights. However, T2DM rats treated with MPT0E014 and control rats had a smaller left ventricular end‑diastolic diameter compared with the T2DM rats. The control and T2DM rats treated with MPT0E014 had greater protein expression of cardiac phosphorylated (p)‑5' adenosine monophosphate‑activated protein kinase α 2, light chain 3‑II, Beclin‑1, glucose transporter 4, p‑protein kinase B, and insulin receptor substrate‑1 (Ser 307) compared with T2DM rats. In addition, control and T2DM rats treated with MPT0E014 had decreased cardiac protein expression of cleaved PARP1, p‑mTOR‑S2448, p‑P70S6K‑Thr‑389, RAGE, tumor necrosis factor‑α, and interleukin‑6 compared with T2DM rats. The present study demonstrated that MPT0E014 may improve cardiac function in T2DM rats by modulating myocardial autophagy, inflammation and insulin signaling.

show abstract

Novel Histone Deacetylase Inhibitor Modulates Cardiac Peroxisome Proliferator-Activated Receptors and Inflammatory Cytokines in Heart Failure

Cited by 32 publications

References 40 publications

Activation of Class I histone deacetylases contributes to mitochondrial dysfunction in cardiomyocytes with altered complex activities

Activation of Class I histone deacetylases contributes to mitochondrial dysfunction in cardiomyocytes with altered complex activities

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

Histone deacetylase inhibition of cardiac autophagy in rats on a high‑fat diet with low‑dose streptozotocin-induced type 2 diabetes mellitus

Contact Info

Product

Resources

About