Abstract 4368380: FYCO1 ameliorates postischemic cardiac remodeling by amplifying autophagic flux and inhibition of proinflammatory pathways

Abstract

Background: Myocardial infarction (MI) triggers transcriptional responses that drive inflammation, metabolic changes and adverse cardiac remodeling. Enhanced autophagic flux is known to limit maladaptive remodeling and improve overall outcomes. FYCO1, a novel regulator of autophagy mediates the transport of autophagosomes and amplifies autophagic flux. Hypothesis: This study aims to investigate whether enhancing autophagic flux via FYCO1 promotes myocardial healing and may improves cardiac outcomes. Methods: FYCO1-Tg mice crossed with RFP-EGFP-LC3 reporter mice (FYCO1-TGxRGFP) were utilized to analyze autophagic flux following permanent ligation of LAD. Autophagy was analyzed via Western blot (p62, LC3 II); macrophage infiltration and apoptosis by immunofluorescence; fibrosis and infarct size by Masson Trichrome staining; and cardiac function by echocardiography. RNA-seq followed by differential expression and Gene Ontology (GO) enrichment analyses of infarcted myocardium identified key pathways altered in response to MI. Results: FYCO1-Tg mice showed increased autophagic flux after MI (p62: WT LAD: 2.9±0.4; TG LAD: 4.0±0.5; LC3 II: WT LAD: 1.6±0.2; TG LAD: 14.0±1.4). Confocal microscopy revealed autolysosome accumulation in WT (autophagosomes: 1±0.4; autolysosomes: 38.6±3.8) versus preserved autophagic flux in transgenic mice (autophagosomes: 43.3±5.1; autolysosomes: 73.5±12.4). Overexpression of FYCO1 significantly reduced fibrosis and infarct size (WT:34,5 ±3,9%; TG:5,5±2%), alongside with improved cardiac function (EF WT: 32,7±3,2%; TG: 56,4±3,9%). RNA-seq in WT mice showed upregulation of genes involved in immune response, cytoskeletal reorganization, and stress adaptation, with downregulation of mitochondrial oxidation and a shift toward glycolysis. In contrast, transgenic mice revealed further upregulation of lysosomal and autophagy pathways and downregulation of mitochondrial oxidative metabolism, ion channel activity, and cytoskeletal binding, consistent with clearance of damaged organelles and a protective metabolic downshift and improved remodeling. These results were confirmed via decreased macrophage infiltration (WT LAD: 132,4 ±14,3; TG LAD: 18,91±3,7 and attenuated apoptosis induction in transgenic mice (cleaved caspase7: WT LAD: 64,6±10,1; TG LAD: 9,2±2,1). Conclusion: In conclusion, FYCO1 mitigates adverse consequences of MI via induction of autophagy and a previously unrecognized role in modulating the pro inflammatory response.