Hypoxia-Inducible Factor-1alpha/BNIP3-Mediated Mitochondrial Autophagy in Septic Cardiomyopathy: Protective Mechanism...

This study aimed to examine the role of hypoxia-inducible factor-1alpha (HIF-1alpha) in septic cardiomyopathy (SCM), focusing on its regulatory function in mitochondrial autophagy. Differentially expressed genes (DEGs) associated with SCM were identified through analysis of the GSE79962 dataset. Mitochondrial autophagy-related genes were retrieved from the GeneCards database. Genes common to both datasets were identified using Venn diagram analysis, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. A murine model of SCM was established via intraperitoneal injection of lipopolysaccharide (LPS). Mice were subsequently treated with either dimethyloxalylglycine (DMOG) a HIF-1alpha stabilizer, or 3-methyladenine (3-MA), an inhibitor of mitochondrial autophagy. Cardiac function, myocardial injury, inflammatory response, mitochondrial integrity, and expression levels of HIF-1alpha and mitochondrial autophagy markers were assessed using echocardiography, enzyme-linked immunosorbent assay (ELISA), hematoxylin-eosin staining, immunofluorescence, transmission electron microscopy, and western blot analysis. KEGG pathway analysis indicated significant enrichment of the overlapping genes in the HIF-1 signaling pathway. In vivo, DMOG administration stabilized HIF-1alpha expression and upregulated Bcl-2-interacting protein 3 (BNIP3), thereby enhancing mitochondrial autophagy. This enhancement was associated with reduced myocardial enzyme release and inflammatory cytokine production, as well as improvements in mitochondrial ultrastructure, myocardial histopathology, and cardiac function. In contrast, 3-MA inhibited mitochondrial autophagy and attenuated the myocardial protective effects associated with HIF-1alpha stabilization. Activation of the HIF-1alpha/BNIP3 signaling axis promotes mitochondrial autophagy and confers protective on cardiac function in septic cardiomyopathy. These findings present a potential mechanistic pathway and therapeutic target for mitigating myocardial injury associated with septic cardiomyopathy.