Histone Deacetylase Inhibition Reduces Pulmonary Vein Arrhythmogenesis through Calcium Regulation

Lkhagva, Baigalmaa; Chang, Shih Lin; Chen, Yao Chang; Kao, Yu Hsun; Lin, Yung Kuo; Chiu, Cindy Tzu Hsuan; Chen, Shih Ann; Chen, Yi Jen

doi:10.1016/j.ijcard.2014.09.175

Cited by 22 publications

(17 citation statements)

References 34 publications

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“…This was the first report documenting the role played by HDACs in atrial remodeling and arrhythmias in animals with structural heart disease. Subsequently, other groups have confirmed our findings and shown that pan-HDAC (Lkhagva et al, 2014) or HDAC6 inhibition can prevent subacute atrial electrical remodeling and inducible AF. Although these results are encouraging, it is not known yet whether HDAC inhibition can oppose the development of sustained AF, the form with higher clinical impact.…”

Section: Introductionsupporting

confidence: 84%

“…Therefore, the fact that inhibiting class I HDACs can reduce existing atrial remodeling and re-establish phases of sinus rhythm during sustained AF is highly significant and may lead to more effective therapies for patients with permanent AF. Previous studies have shown that HDAC inhibitors oppose electrical and structural remodeling (Liu et al, 2008;Lkhagva et al, 2014;Zhang et al, 2014), but none of them tested these effects in a model of sustained AF.…”

Section: Discussionmentioning

confidence: 99%

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Class I Histone Deacetylase Inhibition for the Treatment of Sustained Atrial Fibrillation

Seki

LaCanna

Powers

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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Current therapies are less effective for treating sustained/permanent versus paroxysmal atrial fibrillation (AF). We and others have previously shown that histone deacetylase (HDAC) inhibition reverses structural and electrical atrial remodeling in mice with inducible, paroxysmal-like AF. Here, we hypothesize an important, specific role for class I HDACs in determining structural atrial alterations during sustained AF. The class I HDAC inhibitor N-acetyldinaline [4-(acetylamino)-N-(2-aminophenyl) benzamide] (CI-994) was administered for 2 weeks (1 mg/kg/day) to Hopx transgenic mice with atrial remodeling and inducible AF and to dogs with atrial tachypacing-induced sustained AF. Class I HDAC inhibition prevented atrial fibrosis and arrhythmia inducibility in mice. Dogs were divided into three groups: 1) sinus rhythm, 2) sustained AF plus vehicle, and 3) sustained AF plus CI-994. In group 3, the time in AF over 2 weeks was reduced by 30% compared with group 2, along with attenuated atrial fibrosis and intra-atrial adipocyte infiltration. Moreover, group 2 dogs had higher atrial and serum inflammatory cytokines, adipokines, and atrial immune cells and adipocytes compared with groups 1 and 3. On the other hand, groups 2 and 3 displayed similar left atrial size, ventricular function, and mitral regurgitation. Importantly, the same histologic alterations found in dogs with sustained AF and reversed by CI-994 were also present in atrial tissue from transplanted patients with chronic AF. This is the first evidence that, in sustained AF, class I HDAC inhibition can reduce the total time of fibrillation, atrial fibrosis, intra-atrial adipocytes, and immune cell infiltration without significant effects on cardiac function.

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Section: Introductionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Class I Histone Deacetylase Inhibition for the Treatment of Sustained Atrial Fibrillation

Seki

LaCanna

Powers

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…PV cardiomyocytes from both control and CKD rabbits were loaded with fluorescent Ca 2+ (10 μmol/L, fluo‐3/AM) for 30 minutes at room temperature, as described previously . Fluo‐3 fluorescence was excited by a 488‐nm line of an argon ion laser.…”

Section: Methodsmentioning

confidence: 99%

Redox and Activation of Protein Kinase A Dysregulates Calcium Homeostasis in Pulmonary Vein Cardiomyocytes of Chronic Kidney Disease

Huang

Chen

Kao

et al. 2017

JAHA

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BackgroundChronic kidney disease (CKD) increases the occurrence of atrial fibrillation and pulmonary vein (PV) arrhythmogenesis. Calcium dysregulation and reactive oxygen species (ROS) enhance PV arrhythmogenic activity. The purposes of this study were to investigate whether CKD modulates PV electrical activity through dysregulation of calcium homeostasis and ROS.Methods and ResultsBiochemical and electrocardiographic studies were conducted in rabbits with and without CKD (induced by 150 mg/kg per day neomycin sulfate and 500 mg/kg per day cefazolin). Confocal microscopy with fluorescence and a whole‐cell patch clamp were applied to study calcium homeostasis and electrical activities in control and CKD isolated single PV cardiomyocytes with or without treatment with H89 (1 μmol/L, a protein kinase A inhibitor) and MPG (N‐[2‐mercaptopropionyl]glycine; 100 μmol/L, a ROS scavenger). The ROS in mitochondria and cytosol were evaluated via intracellular dye fluorescence and lipid peroxidation. CKD rabbits had excessive atrial premature captures over those of control rabbits. Compared with the control, CKD PV cardiomyocytes had a faster beating rate and larger calcium transient amplitudes, sarcoplasmic reticulum calcium contents, sodium/calcium exchanger currents, and late sodium currents but smaller L‐type calcium current densities. CKD PV cardiomyocytes had a higher frequency and longer duration of calcium sparks and more ROS in the mitochondria and cytosol than did controls. Moreover, H89 suppressed all calcium sparks in CKD PV cardiomyocytes, and H89‐ and MPG‐treated CKD PV cardiomyocytes had similar calcium transients compared with control PV cardiomyocytes.Conclusions CKD increases PV arrhythmogenesis with enhanced calcium‐handling abnormalities through activation of protein kinase A and ROS.

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“…[41, 42] The Fluo-3 fluorescence was excited with a 488-nm line of an argon ion laser. The emission was recorded at > 515 nm.…”

Section: Methodsmentioning

confidence: 99%

Fibroblast growth factor 23 dysregulates late sodium current and calcium homeostasis with enhanced arrhythmogenesis in pulmonary vein cardiomyocytes

et al. 2016

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Fibroblast growth factor 23 (FGF23), elevated in chronic renal failure, increases atrial arrhythmogenesis and dysregulates calcium homeostasis. Late sodium currents (INa-Late) critically induces ectopic activity of pulmoanry vein (the most important atrial fibrillation trigger). This study was to investigate whether FGF23 activates the INa-Late leading to calcium dysregulation and increases PV arrhythmogenesis. Patch clamp, western blot, and confocal microscopy were used to evaluate the electrical activities, calcium homeostasis, and mitochondrial reactive oxygen species (ROS) in PV cardiomyocytes with or without FGF23 (0.1 or 1 ng/mL) incubation for 4~6 h. Compared to the control, FGF23 (1 ng/mL, but not 0.1 ng/mL)-treated PV cardiomyocytes had a faster beating rate. FGF23 (1 ng/mL)-treated PV cardiomyocytes had larger INa-Late, calcium transients, and mitochondrial ROS than controls. However, ranolazine (an inhibitor of INa-Late) attenuated FGF23 (1 ng/mL)-increased beating rates, calcium transients and mitochondrial ROS. FGF23 (1 ng/mL)-treated PV cardiomyocytes exhibited larger phosphorylation of calcium/calmodulin-dependent protein kinase II (CaMKII). Chelerythrine chloride (an inhibitor of protein kinase C) decreased INa-Late in FGF23 (1 ng/mL)-treated PV cardiomyocytes. However, KN93 (a selective CaMKII blocker) decreased INa-Late in control and FGF23 (1 ng/mL)-treated PV cardiomyocytes to a similar extent. In conclusion, FGF23 increased PV arrhythmogenesis through sodium and calcium dysregulation by acting protein kinase C signaling.

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Histone Deacetylase Inhibition Reduces Pulmonary Vein Arrhythmogenesis through Calcium Regulation

Cited by 22 publications

References 34 publications

Class I Histone Deacetylase Inhibition for the Treatment of Sustained Atrial Fibrillation

Class I Histone Deacetylase Inhibition for the Treatment of Sustained Atrial Fibrillation

Redox and Activation of Protein Kinase A Dysregulates Calcium Homeostasis in Pulmonary Vein Cardiomyocytes of Chronic Kidney Disease

Fibroblast growth factor 23 dysregulates late sodium current and calcium homeostasis with enhanced arrhythmogenesis in pulmonary vein cardiomyocytes

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