A Multifunctional Therapeutic Peptide Attenuates Post-Myocardial Infarction Remodeling Through Antioxidant, Pro-Angiogenic, and Immunomodulatory Mechanisms

Background: Myocardial infarction (MI) triggers excessive oxidative stress, inflammatory activation, and maladaptive fibrosis, leading to adverse ventricular remodeling and heart failure. Therapeutic strategies capable of simultaneously modulating oxidative, inflammatory, and angiogenic pathways remain limited. This study investigates the cardioprotective effects of a novel Multifunctional Peptide (MFP) engineered to possess antioxidant, anti-inflammatory, pro-angiogenic, and endothelial-regenerative activities in a rat model of MI. Methods: Adult male Sprague–Dawley rats underwent left anterior descending (LAD) coronary artery ligation to induce MI, followed by intramyocardial administration of MFP into peri-infarct myocardium. Cardiac remodeling and function were assessed via echocardiography and histopathology at 4 weeks post-MI. Macrophage phenotypes, fibrosis, angiogenesis, and apoptosis were evaluated using immunohistochemistry. In vitro studies examined MFP-mediated cytoprotection in H9C2 cardiomyocytes under oxidative stress and its effects on macrophage polarization in RAW 264.7 cells. RNA-sequencing was performed to identify transcriptomic signatures regulated by MFP. Results: MFP treatment significantly improved left ventricular systolic function and attenuated post-MI structural deterioration. Histological analyses showed reduced cardiomyocyte apoptosis, diminished interstitial fibrosis, and markedly increased capillary density. MFP decreased pro-inflammatory macrophage infiltration while promoting reparative M2 macrophage polarization in vivo. In vitro, MFP protected cardiomyocytes against oxidative damage and enhanced M2-polarizing signaling in macrophages. Transcriptomic profiling revealed downregulation of genes associated with necrosis, inflammation, and adverse remodeling, and upregulation of pathways related to tissue repair, angiogenesis, and immune modulation. Conclusion: MFP confers robust cardioprotection after MI by coordinating the suppression of oxidative stress and inflammation with the enhancement of angiogenic and reparative pathways. These findings support MFP as a promising therapeutic candidate for limiting infarct injury and improving myocardial repair.