N -Acetylcysteine Treatment Restores the Protective Effect of Heart Ischemic Postconditioning in a Murine Model in the Early Stages of Atherosclerosis

<b>Background/Objectives:</b> 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 <i>N</i>-acetylcysteine (NAC), a glutathione precursor with antioxidant properties, can restore the infarct-limiting effect of IP compromised by HFD-induced oxidative stress. <b>Methods:</b> 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. <b>Results:</b> 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%, <i>p</i> < 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. <b>Conclusions:</b> 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

Abstract licence: CC BY

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