Lipoxin A4 improves myocardial ischemia/reperfusion injury through the Notch1-Nrf2 signaling pathway

This study investigates the mechanism by which lipoxin A4 (LXA4) attenuates myocardial ischemia/reperfusion injury (MIRI). Using a rat MIRI model, we evaluated coronary flow, histopathology, cardiac enzymes (cTnI/CK-MB), oxidative stress markers (superoxide dismutase, SOD; malondialdehyde, MDA; glutathione peroxidase, GSH-Px), and protein expression (neurogenic locus notch homolog protein 1 [Notch1], hairy and enhancer of split 1 [Hes1], nuclear factor-erythroid 2-related factor 2 [Nrf2], β-tubulin). Pharmacological inhibitors N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycinet-butylester (DAPT; Notch1) and ML385 (Nrf2) were co-administered with LXA4. Results demonstrated that I/R injury significantly increased microtubule disruption (48.5 ± 6.7% vs control 4.8 ± 0.9%; p < 0.01), decreased SOD (42.1 ± 5.3 vs 89.6 ± 8.7 U/mg), and GSH-Px (15.2 ± 2.1 vs 34.8 ± 4.5 U/mg), and elevated MDA (6.9 ± 0.8 vs 2.1 ± 0.3 nmol/mg; p < 0.05). Notch1, Hes1, and nuclear Nrf2 decreased by 58, 63, and 52%, respectively. LXA4 treatment reversed these effects (23.6 ± 3.6% microtubule disruption; p < 0.05), with DAPT or ML385 abolishing LXA4's protection. These findings indicate that LXA4 protects against MIRI by preserving microtubule integrity and activating the Notch1/Hes1/Nrf2 pathway, revealing a novel mechanism for oxidative stress suppression in cardiomyocytes.