CTSB-associated inflammation and macrophage interaction in heart failure following myocardial infarction and potential therapeutic implications of quercetin
Abstract
Post-myocardial infarction inflammation and maladaptive remodeling are major drivers of heart failure, but the role of cathepsin B (CTSB) in quercetin-associated cardioprotection remains unclear. In this study, public bulk transcriptomic and single-cell RNA sequencing datasets were re-analyzed to characterize CTSB expression across cardiac cell populations and heart failure phenotypes. Network pharmacology and molecular docking were used to explore a potential association between quercetin and CTSB. In lipopolysaccharide-stimulated RAW264.7 macrophage-neonatal rat ventricular myocyte (NRVMs) co-cultures, quercetin reduced nitric oxide production, suppressed inflammatory cytokine expression, promoted a shift toward CD206-positive macrophages, and decreased CTSB expression at both messenger RNA and protein levels. CTSB knockdown reproduced part of the anti-inflammatory phenotype, whereas CTSB overexpression partially attenuated the suppressive effects of quercetin on inflammatory cytokines, supporting CTSB as a functionally relevant mediator contributing to quercetin responsiveness. In a mouse left anterior descending coronary artery ligation model, quercetin improved cardiac functional parameters, reduced infarct-related histopathological injury, decreased myocardial CTSB protein expression, and lowered pro-inflammatory cytokine levels. Molecular docking suggested a potential interaction between quercetin and CTSB, although direct biochemical target engagement was not…
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