Persistent Ferroptosis Modulates Cardiac Remodeling and M2 Macrophage Polarization, Which Can be Mitigated by Astaxanthin During Myocardial Infarction Recovery.

Abstract

The role of ferroptosis, an iron-dependent lipid peroxidation regulated cell death pathway, remains obscure during myocardial infarction (MI) recovery. Our study aims to clarify ferroptosis' function in post-MI cardiac recovery, explore the consequences of iron overload and ferroptosis for myocardial remodeling, and assess the effects of Liproxstatin-1 (Lipro-1) treatment on macrophage functionality. Moreover, we examine the potential of Astaxanthin (ASTX), recognized for its antioxidative properties, to mitigate ferroptosis during MI recovery and its subsequent ramifications for myocardial remodeling. Our results demonstrate persistent ferroptosis during MI recovery, marked by decreased Glutathione Peroxidase 4 and increased Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) and Ferroportin 1 alongside elevated lipid peroxidation and iron levels up to D21. We identified a significant correlation between ferroptosis and macrophage activity, noted by the increase in macrophage populations co-expressing GPX4 and ACSL4 markers in the peri-infarct area by D21. Liproxstatin-1 treatment reduced macrophage (CD68 +) counts, promoted M2 polarization decreased inflammation, and improved cardiac function. Myocardial remodeling was improved in Lipro-1-treated rats, as shown by decreased fibrosis and reduced levels of α-SMA, Collagen I, and Collagen III proteins. ASTX treatment also exhibited an inhibiting effect on ferroptosis indicators, and encouraged M2 macrophage polarization, reduced inflammation, and enhanced both cardiac function and myocardial remodeling, mirroring the beneficial effects observed with Lipro-1. In summary, the interactions between ferroptosis, macrophage polarization, and myocardial remodeling are crucial for cardiac function improvement post-MI. Lipro-1 and ASTX emerge as promising therapeutic agents by modulating post-MI ferroptosis and related immune responses.