Zaobornyj Tamara, Perez Virginia, Ossani Georgina, Mazo Tamara, Godoy Eugenia, Godoy Jorge, Yanaje Yohana, Musci-Ferrari Camila, Contin Mario, Tripodi Valeria, Barchuk Magali, Berg Gabriela, Gelpi Ricardo J, Donato Martin, D'Annunzio Veronica
Instituto de Bioquímica y Medicina Molecular (IBIMOL UBA-CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires 1113, Argentina.
Instituto de Fisiopatología Cardiovascular (INFICA), Facultad de Ciencias Médicas, Universidad de Buenos Aires, Buenos Aires 1114, Argentina.
Pharmaceuticals (Basel). 2025 Jul 8;18(7):1014. doi: 10.3390/ph18071014.
Ischemic postconditioning (IP) is a well-established intervention that mitigates this damage by activating endogenous cardioprotective pathways. However, the presence of comorbidities such as dyslipidemia can disrupt these protective mechanisms and abolish the infarct-sparing effect typically induced by IP. In this context, identifying pharmacological strategies to restore cardioprotection is of clinical relevance. This study aimed to evaluate whether -acetylcysteine (NAC), a glutathione precursor with antioxidant properties, can restore the infarct-limiting effect of IP compromised by HFD-induced oxidative stress. Male mice were fed a control diet (CD) or HFD for 12 weeks. NAC (10 mM) was administered in drinking water for 3 weeks before ex vivo myocardial ischemia/reperfusion (I/R) injury (30 min ischemia/60 min reperfusion). In IP groups, six cycles of brief I/R were applied at the onset of reperfusion. Infarct size, ventricular function, redox status (GSH/GSSG), lipid profile, and histology were evaluated. NAC improved the lipid profile (HDL/non-HDL ratio) and enhanced the infarct-sparing effect of IP in CD-fed mice. In HFD-fed mice, NAC restored the efficacy of IP, significantly reducing infarct size (HFD-I/R-NAC: 39.7 ± 4.5% vs. HFD-IP-NAC: 26.4 ± 2.0%, < 0.05) without changes in ventricular function. The ratio of oxidized/reduced glutathione (GSSG/GSH) is depicted. Under basal conditions, the hearts of mice fed an HFD exhibited a shift towards a more oxidized state compared to the control diet CD group. In the I/R protocol, a significant shift towards a more oxidized state was observed in both CD and HFD-fed animals. In the IP protocol, the GSSG/GSH ratio revealed a tendency to basal values in comparison to the I/R protocol. The analysis indicates that animals subjected to I/R and IP protocols in conjunction with NAC show a tendency to reach basal values, thus suggesting a potential for the reduction in ROS. NAC treatment mitigates oxidative stress and restores the cardioprotective effect of ischemic postconditioning in a model of early-stage atherosclerosis. These findings support NAC as a potential adjunct therapy to improve myocardial resistance to reperfusion injury under dyslipidemic conditions.
缺血后处理（IP）是一种成熟的干预措施，通过激活内源性心脏保护途径减轻这种损伤。然而，诸如血脂异常等合并症的存在会破坏这些保护机制，并消除IP通常诱导的梗死面积缩小效应。在此背景下，确定恢复心脏保护作用的药理学策略具有临床意义。本研究旨在评估具有抗氧化特性的谷胱甘肽前体——N-乙酰半胱氨酸（NAC）是否能恢复因高脂饮食诱导的氧化应激而受损的IP的梗死面积限制效应。雄性小鼠喂食对照饮食（CD）或高脂饮食12周。在离体心肌缺血/再灌注（I/R）损伤（30分钟缺血/60分钟再灌注）前3周，在饮用水中给予NAC（10 mM）。在IP组中，在再灌注开始时施加6个周期的短暂I/R。评估梗死面积、心室功能、氧化还原状态（GSH/GSSG）、血脂谱和组织学。NAC改善了血脂谱（HDL/非HDL比值），并增强了喂食CD小鼠中IP的梗死面积缩小效应。在喂食高脂饮食的小鼠中，NAC恢复了IP的疗效，显著减小了梗死面积（高脂饮食-I/R-NAC：39.7±4.5% vs. 高脂饮食-IP-NAC：26.4±2.0%，P<0.05），而心室功能无变化。描绘了氧化型/还原型谷胱甘肽（GSSG/GSH）的比值。在基础条件下，与对照饮食CD组相比，喂食高脂饮食的小鼠心脏呈现出向更氧化状态的转变。在I/R方案中，在喂食CD和高脂饮食的动物中均观察到向更氧化状态的显著转变。在IP方案中，与I/R方案相比，GSSG/GSH比值显示出趋向于基础值的趋势。分析表明，接受I/R和IP方案并联合NAC处理的动物呈现出趋向于基础值的趋势，因此提示有降低活性氧的潜力。NAC处理减轻了氧化应激，并在早期动脉粥样硬化模型中恢复了缺血后处理的心脏保护作用。这些发现支持NAC作为一种潜在的辅助治疗方法，以改善血脂异常情况下心肌对再灌注损伤的耐受性。
