Heart and Vascular Center, Semmelweis University, Budapest, Hungary.
Department of Cardiac Surgery, University of Heidelberg, Heidelberg, Germany.
Sci Rep. 2017 Oct 27;7(1):14232. doi: 10.1038/s41598-017-14587-3.
While heart transplantation (HTX) is the definitive therapy of heart failure, donor shortage is emerging. Pharmacological activation of soluble guanylate cyclase (sGC) and increased cGMP-signalling have been reported to have cardioprotective properties. Gemfibrozil has recently been shown to exert sGC activating effects in vitro. We aimed to investigate whether pharmacological preconditioning of donor hearts with gemfibrozil could protect against ischemia/reperfusion injury and preserve myocardial function in a heterotopic rat HTX model. Donor Lewis rats received p.o. gemfibrozil (150 mg/kg body weight) or vehicle for 2 days. The hearts were explanted, stored for 1 h in cold preservation solution, and heterotopically transplanted. 1 h after starting reperfusion, left ventricular (LV) pressure-volume relations and coronary blood flow (CBF) were assessed to evaluate early post-transplant graft function. After 1 h reperfusion, LV contractility, active relaxation and CBF were significantly (p < 0.05) improved in the gemfibrozil pretreated hearts compared to that of controls. Additionally, gemfibrozil treatment reduced nitro-oxidative stress and apoptosis, and improved cGMP-signalling in HTX. Pharmacological preconditioning with gemfibrozil reduces ischemia/reperfusion injury and preserves graft function in a rat HTX model, which could be the consequence of enhanced myocardial cGMP-signalling. Gemfibrozil might represent a useful tool for cardioprotection in the clinical setting of HTX surgery soon.
虽然心脏移植（HTX）是心力衰竭的确定性治疗方法，但供体短缺正在出现。已报道可溶性鸟苷酸环化酶（sGC）的药理学激活和 cGMP 信号的增加具有心脏保护特性。吉非贝齐最近已被证明具有体外激活 sGC 的作用。我们旨在研究吉非贝齐对供体心脏的药理学预处理是否可以防止缺血/再灌注损伤并在同种异体大鼠 HTX 模型中保护心肌功能。供体 Lewis 大鼠接受 p.o. 吉非贝齐（150mg/kg 体重）或载体 2 天。取出心脏，在冷保存液中储存 1 小时，并进行异位移植。再灌注开始后 1 小时，评估左心室（LV）压力-容积关系和冠状动脉血流量（CBF），以评估移植后早期移植物功能。与对照组相比，吉非贝齐预处理心脏的 LV 收缩性、主动松弛和 CBF 在再灌注 1 小时后显著（p<0.05）改善。此外，吉非贝齐治疗减少了硝基氧化应激和细胞凋亡，并改善了 HTX 中的 cGMP 信号。吉非贝齐的药理学预处理可减少缺血/再灌注损伤并保护大鼠 HTX 模型中的移植物功能，这可能是心肌 cGMP 信号增强的结果。吉非贝齐可能很快成为 HTX 手术临床环境中心脏保护的有用工具。
