Br J Pharmacol. 2026 Jan 12. doi: 10.1111/bph.70320. Online ahead of print.
ABSTRACT
BACKGROUND AND PURPOSE: LCZ696 (sacubitril/valsartan) can attenuate early cardiac remodelling of heart failure (HF), although it is less effective in severe remodelling. Surgical ventricular reconstruction (SVR) is used to treat refractory HF with large ventricular aneurysms (LVA), but residual remodelling limits the long-term survival. It is unknown whether LCZ696 can mitigate residual remodelling.
EXPERIMENTAL APPROACH: Male C57BL/6 mice were subjected to myocardial infarction (MI) or sham surgery. Four weeks later, MI mice with LVA underwent SVR or a second open-chest operation, followed by randomisation to LCZ696 or vehicle. Echocardiography, histological analysis, and immunofluorescence staining were used to evaluate heart function, cardiac remodelling, and myocardial proliferation. Molecular docking, RNA pull-down, and RNA protein immunoprecipitation were used to explore downstream mechanisms. Non-targeted metabolomics and bioinformatics analysis were used to characterise metabolic changes.
KEY RESULTS: LCZ696 significantly attenuated residual remodelling and further enhanced cardiomyocyte proliferation in SVR mice, but not MI mice, as evidenced by positive staining of Ki-67, phospho-histone H3, and Aurora B in the plication zone. LCZ696 increased circMap4k2 expression in SVR hearts. Silencing of circMap4k2 inhibited the efficacy of LCZ696 on improving SVR residual remodelling and cardiac proliferation, whereas overexpression of circMap4k2 promoted it. Mechanistically, circMap4k2 bound to LIN28 homologue A (LIN28A), elevating pyruvate dehydrogenase kinase 1 (PDK1) expression, thereby promoting glycolysis and reducing residual remodelling. LCZ696 reprogrammes cardiac metabolism after SVR, with 195 metabolites up-regulated and 99 down-regulated.
CONCLUSION AND IMPLICATIONS: LCZ696 induces glycolysis, promotes myocardial repair, and alleviates residual remodelling of SVR by targeting the circMap4k2/LIN28A/PDK1 pathway.
PMID:41527427 | DOI:10.1111/bph.70320