Galectin-3 associates with NF-κB activation and mitochondrial redox–related protein signatures in catecholamine-induced stress cardiomyopathy

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BACKGROUND: Acute catecholamine-induced myocardial stress contributes to several cardiac conditions, including takotsubo syndrome (TS), a life-threatening acute cardiac syndrome characterized by transient regional left ventricular dysfunction that lacks evidence-based therapy. Extracellular vesicles (EVs) reflect active cellular stress signaling and enable region-specific analysis of myocardial stress responses to acute injury. Galectin-3 (Gal-3) regulates inflammation and myocardial remodeling and predicts adverse outcomes in myocardial infarction and heart failure, yet its role in catecholamine-driven stress cardiomyopathy, including TS, remains unclear. OBJECTIVES: To characterize regional myocardial stress signaling after catecholamine exposure using cardiac EV proteomics and to determine whether Gal-3–linked stress pathways are associated with the TS-like apical akinesia phenotype. METHODS AND RESULTS: Catecholamine-induced stress was induced in rats by isoprenaline administration and cardiac function was evaluated by echocardiography. EVs were isolated from apical and basal regions of the left ventricular myocardium using enzymatic digestion, differential centrifugation, and iodixanol purification. EVs were characterized by transmission electron microscopy, western blotting, and nanoparticle tracking analysis. EV protein abundance was quantified using TMTpro 18-plex LC–MS/MS and analyzed for stress and region-specific differences. EV proteomics analysis showed significant enrichment of Gal-3 in EVs isolated from the apical left ventricular myocardium after catecholamine stress and associated Gal-3 with inflammatory (TNF/TLR4-NF-κB-related) and mitochondrial and redox-related signatures. In cardiomyoblasts, recombinant Gal-3 increased NF-κB p65 Ser536 phosphorylation and reduced expression of antioxidant (Sod3) and mitochondrial biogenesis related (Ppargc1a) transcripts, while inhibition of Gal-3 attenuated TNF-α-induced NF-κB activation and suppressed isoprenaline-induced inflammatory gene expression. In vivo, myocardial Gal-3 increased after isoprenaline exposure, but did not differ between animals with or without TS-like apical akinesia, suggesting association with neurohumoral stress exposure rather than the TS-like contractile phenotype. CONCLUSIONS: Gal-3 is upregulated following acute catecholamine exposure and is associated with inflammatory and mitochondrial redox signaling during myocardial stress. Although myocardial Gal-3 increased after isoprenaline exposure it was not associated with the TS-like contractile phenotype, indicating that Gal-3 reflects catecholamine-induced myocardial stress rather than determining regional contractile dysfunction.

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