Key Laboratory of Advanced Drug Preparation Technologies, Ministry of Education of China, Co-innovation Center of Henan Province for New drug R & D and Preclinical Safety, School of Pharmaceutical Sciences, PR China.
School of Chemistry and Molecular Engineering, Zhengzhou University, PR China.
J Mol Cell Cardiol. 2019 Oct;135:52-66. doi: 10.1016/j.yjmcc.2019.07.014. Epub 2019 Jul 27.
(±)-Sodium5-bromo-2-(α-hydroxypentyl) benzoate (brand name: brozopine, BZP, 1a), derived from L-3-n-butylphthalide (L-NBP), has been reported to protect the brain from stoke and has been approved by CFDA in Phase I-II clinical trials. However, it remains to be investigated whether 1a may exhibit any cardioprotective effect on ischemia-reperfusion (I/R) injury. In the current study, C57BL/6 and ICR mice were pretreated with 1a, and myocardium I/R were then performed. We found that 1a not only significantly reduced the infarct size and improved cardiac contractile function after acute MI/R in both species, but also protected hearts from chronic MI-related cardiac injury. Mechanically, we found that 1a physically binds to 12/15-LOX-2 using molecular docking. The shRNA-mediated 12/15-LOX-2 knockdown almost completely blocked the protective effect of 1a. Our findings, for the first time, strongly indicate that 1a may serve as a potent and promising cardioprotective agent in treatment of I/R related injury, at least partially through targeting 12/15-LOX-2.
（±）-Sodium5-bromo-2-(α-hydroxypentyl) benzoate（商品名：bropzopine，BZP，1a），来源于 L-3-n-丁基邻苯二甲酸内酯（L-NBP），已被报道能保护大脑免受中风的影响，并已通过 CFDA 的 I-III 期临床试验。然而，1a 是否对缺血再灌注（I/R）损伤具有任何心脏保护作用仍有待研究。在本研究中，用 1a 预处理 C57BL/6 和 ICR 小鼠，然后进行心肌 I/R。我们发现 1a 不仅显著减少了两种物种急性 MI/R 后的梗死面积和改善了心肌收缩功能，而且还保护心脏免受慢性 MI 相关的心脏损伤。在机制上，我们发现 1a 使用分子对接与 12/15-LOX-2 物理结合。shRNA 介导的 12/15-LOX-2 敲低几乎完全阻断了 1a 的保护作用。我们的研究结果首次强烈表明，1a 可能作为一种有效的、有前途的心脏保护剂用于治疗 I/R 相关损伤，至少部分是通过靶向 12/15-LOX-2。
