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106年7月 博士班畢業生 Baigalmaa 博士畢業論文摘要

學術焦點
張貼人:何佳芸公告日期:2018-02-27
1
                                                                                   Histone Deacetylase Inhibition:

A Novel Treatment for Cardiac Electrical and Structural Disorders

Atrial fibrillation (AF) is a common cardiac arrhythmia associated with high mortality and morbidity. Current treatments of AF have limited efficacy and considerable side effects. Histone deacetylase (HDACs) play critical roles in the pathophysiology of cardiovascular diseases and contribute to calcium homeostasis and AF genesis. Therefore, HDAC inhibition may prove a novel therapeutic strategy for AF through upstream therapy and modifications of AF electrical and structural remodeling. However, the electrophysiological effects of HDAC inhibition were unclear. Pulmonary veins (PVs) are the most important ectopic foci for AF and play a critical role in the pathophysiology of AF. Modulating PV calcium homeostasis controls PV electrical activity, which may reduce the risk of AF. Therefore, first, we investigated whether HDAC inhibition can regulate PV electrical activity through calcium modulation. Second, we evaluated whether HDAC inhibition can regulate heart failure (HF) by modifying cardiac inflammation and peroxisome-proliferator-activated receptor (PPAR) isoforms. In study I, Whole-cell patch-clamp, confocal microscopic, and Western blot were used to evaluate electrophysiological characteristics and calcium dynamics in isolated rabbit PV cardiomyocytes with and without MPT0E014 (a pan HDAC inhibitor), MS-275 (HDAC1 and 3 inhibitor), and MC-1568 (HDAC4 and 6 inhibitor) for 5~8 h. Atrial electrical activity and induced-AF were measured in rabbits with and without MPT0E014 (10 mg/kg treated for 5 hours). In study II, echocardiography, electrocardiography, ELISA, and Western blot were performed in rats with isoproterenol-induced HF with and without orally administered MPT0E014 (50 mg/kg for 7 consecutive days). Study I showed that MPT0E014 (1 µM)-treated PV cardiomyocytes had slower beating rates than control PV cardiomyocytes. However, control and MPT0E014 (1 µM)-treated sinoatrial node cardiomyocytes had similar beating rates. MS-275-treated PV cardiomyocytes, but not MC-1568-treated PV cardiomyocytes had slower beating rates than control PV cardiomocytes. MPT0E014-treated PV cardiomyocytes had a lower frequency of calcium sparks than control PV cardiomyocytes. As compared to control, MPT0E014-treated PV cardiomyocytes had reduced calcium transient amplitudes, sodium-calcium exchanger currents, and ryanodine receptor expressions. Moreover, MPT0E014-treated rabbits had less AF and shorter AF duration than control rabbits. In study II, the left ventricles (LVs) of HF rats expressed significantly higher HDAC1, HDAC2, HDAC3, HDAC4 and HDAC6 than the healthy LVs did. HF rats treated with MPT0E014 exhibited improved cardiac fraction shortening with reducing chamber size. The MPT0E014-treated HF LVs exhibited a smaller increase in the expression of interleukin-6, p22, SMAD2/3, extracellular signal-regulated kinase 1/2, PPAR isoforms, and circulatory tumor growth factor-β1 than the untreated HF LVs did. Moreover, MPT0E014-treated HF LVs expressed less fibroblast growth factor receptor than untreated HF LVs did. Our study results show that HDAC inhibition reduced PV arrhythmogenesis and AF inducibility with modulation on calcium homeostasis. Therefore, HDAC inhibition can improve cardiac function and attenuate the effects of HF on cardiac metabolism and inflammation, which might contribute to the beneficial effects of HDAC inhibition in AF through multiple target modifications.

 

入學年月:1009
畢業年月:1068
指導教授: 陳亦仁、高玉勳

最後修改時間:2018-03-12 AM 4:15

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