Department of Pharmacy, Tongji Hospital, Tongji University School of Medicine, Shanghai, China; School of Pharmacy, Macau University of Science and Technology, Macau, China.
Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China; Mitochondria and Metabolism Center, Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, USA.
Redox Biol. 2018 May;15:243-252. doi: 10.1016/j.redox.2017.11.020. Epub 2017 Dec 14.
Therapeutic strategies that increase hydrogen sulfide (HS) or nitric oxide (NO) are cytoprotective in various models of cardiovascular injury. However, the nature of interaction between HS and NO in heart failure and the underlying mechanisms for the protective effects remain undefined. The present study tested the cardioprotective effect of ZYZ-803, a novel synthetic HS-NO hybrid molecule that decomposed to release HS and NO. ZYZ-803 dose dependently improved left ventricular remodeling and preserved left ventricular function in the setting of isoprenaline-induced heart failure. The cardioprotective effect of ZYZ-803 is significantly more potent than that of HS and/or NO donor alone. ZYZ-803 stimulated the expression of cystathionine γ-lyase (CSE) for HS generation and the activity of endothelial NO synthase (eNOS) for NO production. Blocking CSE and/or eNOS suppressed ZYZ-803-induced HS and NO production and cardioprotection. ZYZ-803 increased vascular endothelial growth factor (VEGF) concentration and cyclic guanosine 5'-monophosphate (cGMP) level. Moreover, ZYZ-803 upregulated the endogenous antioxidants, glutathione peroxidase (GPx) and heme oxygenase 1 (HO-1). These findings indicate that HS and NO cooperatively attenuates left ventricular remodeling and dysfunction during the development of heart failure through VEGF/cGMP pathway and ZYZ-803 provide expanding insight into strategies for treatment of heart failure.
在各种心血管损伤模型中，增加硫化氢 (HS) 或一氧化氮 (NO) 的治疗策略具有细胞保护作用。然而，HS 和 NO 在心衰中的相互作用性质以及保护作用的潜在机制仍未确定。本研究测试了一种新型合成的 HS-NO 混合分子 ZYZ-803 的心脏保护作用，该分子分解后释放 HS 和 NO。ZYZ-803 剂量依赖性地改善了异丙肾上腺素诱导的心力衰竭中的左心室重构并保留了左心室功能。ZYZ-803 的心脏保护作用明显强于 HS 和/或单独的 NO 供体。ZYZ-803 刺激胱硫醚 γ-裂解酶 (CSE) 的表达以产生 HS，并刺激内皮型一氧化氮合酶 (eNOS) 的活性以产生 NO。阻断 CSE 和/或 eNOS 抑制了 ZYZ-803 诱导的 HS 和 NO 产生和心脏保护作用。ZYZ-803 增加了血管内皮生长因子 (VEGF) 浓度和环鸟苷酸 5'-单磷酸 (cGMP) 水平。此外，ZYZ-803 上调了内源性抗氧化剂谷胱甘肽过氧化物酶 (GPx) 和血红素加氧酶 1 (HO-1)。这些发现表明，HS 和 NO 通过 VEGF/cGMP 途径协同减轻心力衰竭发展过程中的左心室重构和功能障碍，而 ZYZ-803 为心力衰竭的治疗策略提供了更深入的认识。
