Jinxinkang granule alleviates chronic heart failure by enhancing GPER/AMPK/PCG-1α-mediated fatty acid oxidation

• JXK improves chronic heart failure in both ISO or MI-induced animal model. • JXK alleviates chronic heart failure by enhancing myocardial energy metabolism. • JXK activates GPER/AMPK/PCG-1α-mediated fatty acid oxidation. Chronic heart failure (CHF) is considered to be the last battlefield of cardiovascular disease. Jinxinkang granule (JXK) is an integrated traditional Chinese medicine formula for treating CHF. Our previous clinical study showed that JXK could increase the left ventricular ejection fraction and reduce concomitant symptoms in patients with CHF. However, the molecular mechanism underlying the action of JXK on CHF has yet to be fully illustrated. Sprague-Dawley (SD) rats under left anterior descending artery ligation model, C57BL/6 mice subcutaneously injected isoproterenol (ISO) model in vivo and H9c2 cells under oxygen glucose deprivation (OGD) in vitro were used to evaluate the effect of JXK against CHF. Cardiac function and morphology assessment using M-mode echocardiography, H&E/Masson/WGA staining, western blotting analysis, real-time PCR detection, ATP and cAMP assays were used to explore the mechanism of JXK against CHF. JXK improved cardiac function and ameliorated cardiac fibrosis in both LAD-induced CHF rats and ISO-induced CHF mice, and protected cardiomyocytes from OGD injury in H9c2 cells. Moreover, JXK increased the level of ATP content and enhanced fatty acid oxidation by increasing CD36, CPT1A and ACADM expression. Mechanism study showed that JXK increased the GPER expression and cAMP level, promoted AMPK phosphorylation and PGC-1α expression. Additionally, molecular docking analysis showed that dihydroisotanshinone I has a high binding affinity with GPER at -8.5 kcal/mol, which has the similar binding sites with G-1, a GPER agonist. Importantly, after using the inhibitor of GPER (G15), the cardioprotective effect of JXK and the enhancing effect on the fatty acid oxidation were blocked. JXK effectively activated GPER/AMPK/PGC-1α signaling pathway to enhance the oxidation of fatty acid, thereby promoting cardiac energy metabolism production to ameliorate CHF.