LCZ696 (sacubitril/valsartan) alleviates residual cardiac remodeling of large ventricular aneurysms after surgical ventricular reconstruction by mediating circMap4k2/LIN28A/PDK1 pathway

Abstract Introduction The treatment of refractory heart failure (HF) with large ventricular aneurysms (LVA) faces difficulties and requires effective therapy. Surgical ventricular reconstruction (SVR) is used to reverse cardiac remodeling for these patients, however, residual remodeling and dysfunction after SVR limits the improvement of HF. Recently, we reported that circMap4k2 promoted cardiac regeneration in the plication zone and attenuated residual remodeling after SVR. LCZ696 (sacubitril/valsartan) can reduce cardiac remodeling in early HF, while efficacy is poor in refractory HF with severe remodeling. It is unclear whether LCZ696 could improve residual remodeling and regulate circMap4k2 after SVR attenuates partial cardiac remodeling. Purpose We aimed to explore whether LCZ696 would reverse residual remodeling after SVR and related mechanisms. Methods Adult Male C57BL/6 mice were subjected to myocardial infarction (MI) or sham surgery. Four weeks later, MI mice with a LVA underwent SVR or a second open-chest operation and were randomized to LCZ696 or vehicle for four-week. Echocardiography and histological analysis were used to evaluate heart function, cardiac remodeling, and myocardial regeneration. Bioinformatics analysis, molecular docking analysis, RNA immunoprecipitation (RIP) and RNA pulldown were used to explore the underlying mechanisms. Results Compared with vehicle-treated SVR and LCZ696-treated non-SVR mice, LCZ696-treated SVR mice had significantly smaller left ventricular volume, better ejection fraction, lower heart-to-body weight ratio, less myocardial fibrosis and more positive staining of Ki-67, phospho-histone H3, and Aurora B in the plication zone. LCZ696 up-regulated the cardiac expression of circMap4k2 in SVR mice. Silencing of circMap4k2 markedly blocked the curative effects of LCZ696 on SVR mice, while overexpression of circMap4k2 enhanced these effects. We predicted 22 proteins that may bind to circMap4k2, among which lin-28 homolog A (LIN28A) had the highest binding potential, and confirmed the combination between circMap4k2 and LIN28A. Mechanistically, LCZ696-induced circMap4k2 bound to LIN28A, increased downstream pyruvate dehydrogenase kinase 1 (PDK1) expression, which activated glycolysis in injured myocardium and ultimately promoted cardiomyocyte proliferation. Conclusions LCZ696 improves cardiac metabolism and increases cardiac regeneration in the plication zone by mediating circMap4k2/LIN28A/PDK1 pathway, thereby attenuating residual remodeling and restoring heart function after SVR.