Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, China.
Key Laboratory of Cardiovascular and Cerebrovascular Medicine, School of Pharmacy, Nanjing Medical University, Nanjing, China.
Br J Pharmacol. 2018 Apr;175(8):1126-1145. doi: 10.1111/bph.13861. Epub 2017 Jul 6.
Hydrogen sulfide (H S) is a gaseous signal molecule with antioxidative properties. Sirtuin 3 (SIRT3) is closely associated with mitochondrial function and oxidative stress. The study was to investigate whether and how H S improved myocardial hypertrophy via a SIRT3-dependent manner.
Neonatal rat cardiomyocytes were pretreated with NaHS (50 μM) for 4 h followed by angiotensin II (Ang II, 100 nM) for 24 h. SIRT3 was silenced with siRNA technology. SIRT3 promoter activity and expression, cell surface, hypertrophic gene mRNA expression, mitochondrial oxygen consumption rate and membrane potential were measured. Male 129S1/SvImJ [wild-type (WT)] and SIRT3 knockout (KO) mice were injected with NaHS (50 μmol·kg ·day ; i.p.) followed by transverse aortic constriction (TAC). Echocardiography, heart mass, mitochondrial ultrastructure, volume and number, oxidative stress, mitochondria fusion and fission-related protein expression were measured.
In vitro, NaHS increased SIRT3 promoter activity and SIRT3 expression in Ang II-induced cardiomyocyte hypertrophy. SIRT3 silencing abolished the ability of NaHS to reverse the Ang II-induced cardiomyocyte hypertrophy, mitochondrial function impairment and permeability potential dysfunction, along with the decline in FOXO3a and SOD2 expression. In vivo, after TAC. NaHS attenuated myocardial hypertrophy, inhibited oxidative stress, improved mitochondrial ultrastructure, suppressed mitochondrial volume but increased mitochondrial numbers, enhanced OPA1, MFN1 and MFN2 expression but suppressed DRP1 and FIS1 expression in WT mice but not in SIRT3 KO mice CONCLUSION AND IMPLICATIONS: NaHS improved mitochondrial function and inhibited oxidative stress in myocardial hypertrophy in a SIRT3-dependent manner.
This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.
硫化氢（H2S）是一种具有抗氧化特性的气体信号分子。Sirtuin 3（SIRT3）与线粒体功能和氧化应激密切相关。本研究旨在探讨 H2S 是否以及如何通过 SIRT3 依赖性方式改善心肌肥大。
用 NaHS（50 μM）预处理新生大鼠心肌细胞 4 h，然后用血管紧张素 II（Ang II，100 nM）处理 24 h。用 siRNA 技术沉默 SIRT3。测量 SIRT3 启动子活性和表达、细胞表面、肥大基因 mRNA 表达、线粒体耗氧率和膜电位。雄性 129S1/SvImJ [野生型（WT）]和 SIRT3 敲除（KO）小鼠腹腔注射 NaHS（50 μmol·kg·day），然后进行主动脉缩窄（TAC）。测量超声心动图、心脏质量、线粒体超微结构、体积和数量、氧化应激、线粒体融合和分裂相关蛋白表达。
在体外，NaHS 增加了 Ang II 诱导的心肌细胞肥大中 SIRT3 启动子活性和 SIRT3 表达。SIRT3 沉默消除了 NaHS 逆转 Ang II 诱导的心肌细胞肥大、线粒体功能障碍和通透性电位功能障碍的能力，同时降低了 FOXO3a 和 SOD2 的表达。在体内，TAC 后，NaHS 减轻了心肌肥大，抑制了氧化应激，改善了线粒体超微结构，抑制了线粒体体积但增加了线粒体数量，增强了 OPA1、MFN1 和 MFN2 的表达，但抑制了 DRP1 和 FIS1 的表达在 WT 小鼠中，但在 SIRT3 KO 小鼠中没有。
NaHS 通过 SIRT3 依赖性方式改善心肌肥大中的线粒体功能并抑制氧化应激。
本文是心血管疾病小分子专题的一部分。要查看该部分中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc。
