Department of Pharmacology, Institute of Pharmacy, Nirma University, Sarkhej-Gandhinagar Highway, Ahmedabad, 382 481, Gujarat, India.
Cardiovasc Toxicol. 2018 Feb;18(1):1-8. doi: 10.1007/s12012-017-9406-2.
The aim of the present research was to study the effect of sodium butyrate (SB) on partial abdominal aorta constriction (PAAC)-induced cardiac hypertrophy and determine its mechanism of action. Healthy Wistar rats were exposed to PAAC for eight weeks. After eight weeks, we carried out hypertrophic and hemodynamic evaluation and measured oxidative stress parameters and mitochondrial DNA concentration. PAAC control animals exhibited cardiac hypertrophy, decreased hemodynamic functions and oxidative stress. Treatment with SB reduced hypertrophic indices, LV wall thickness, LV collagen levels, cardiomyocyte diameter, serum lipid levels and serum cardiac biomarkers. Treatment with SB also improved hemodynamic functions, prevented oxidative stress and increased mitochondrial DNA concentration. Improvement in hypertrophy due to HDAC inhibition was further confirmed by HDAC mRNA expression studies which revealed that SB decreases expression of prohypertrophic HDAC, i.e., HDAC2, without altering the expression of anti-hypertrophic HDAC5. Sodium butyrate produces beneficial effect on cardiac hypertrophy as is evident, specifically from reduction in hypertrophic parameters including collagen levels, improvement in mitochondrial DNA concentration and preservation of LV systolic and diastolic dysfunction. This beneficial effect of sodium butyrate is mediated through downregulation of class I HDACs, specifically HDAC2 without any effect on class II HDAC, i.e., HDAC5. Thus, selective class I HDAC inhibition is required for controlling cardiac hypertrophy. Newer HDAC inhibitors which are class I inhibitor and class II promoter can be designed to obtain a 'pan' or 'dual' natural HDAC 'regulators.'
本研究旨在探讨丁酸钠（SB）对部分腹主动脉缩窄（PAAC）诱导的心肌肥厚的影响，并确定其作用机制。健康 Wistar 大鼠接受 PAAC 处理 8 周。8 周后，我们进行了肥厚和血流动力学评估，并测量了氧化应激参数和线粒体 DNA 浓度。PAAC 对照组动物表现出心肌肥厚、血流动力学功能降低和氧化应激。SB 治疗降低了肥厚指数、LV 壁厚度、LV 胶原水平、心肌细胞直径、血清脂质水平和血清心脏生物标志物。SB 治疗还改善了血流动力学功能，预防了氧化应激并增加了线粒体 DNA 浓度。HDAC 抑制对肥厚的改善作用进一步通过 HDAC mRNA 表达研究得到证实，该研究表明 SB 降低了促肥厚 HDAC（即 HDAC2）的表达，而不改变抗肥厚 HDAC5 的表达。丁酸钠对心肌肥厚有有益的影响，这一点很明显，特别是从减少肥厚参数，包括胶原水平，改善线粒体 DNA 浓度和保留 LV 收缩和舒张功能障碍。丁酸钠的这种有益作用是通过下调 I 类 HDACs 介导的，特别是 HDAC2，而对 II 类 HDAC，即 HDAC5 没有影响。因此，需要选择性地抑制 I 类 HDAC 来控制心肌肥厚。可以设计新型的 I 类 HDAC 抑制剂和 II 类促进剂，以获得“泛”或“双重”天然 HDAC“调节剂”。
