LCZ696 Ameliorates Cardiac Function via the Akt/FoxO1 Signaling Pathway in Rats with Diabetic Cardiomyopathy

Abstract

Background: Diabetic cardiomyopathy (DCM) is a condition that is characterized by impairment in both systolic and diastolic cardiac functions. Inflammation, apoptosis, interstitial fibrosis, and oxidative stress are the primary ultrastructural alterations in DCM. LCZ696 which has been reported to protect against DCM, contains two molecular components, is a novel anti-heart failure medication that combines a neprilysin inhibitor and an angiotensin receptor blocker. This study aimed to examine the effect of LCZ696 on heart function in a rat model of diabetic heart disease, with a particular emphasis on the Protein Kinase B (Akt)/Forkhead box O1 (FoxO1) signaling pathway. Methods: We induced diabetes in male Wistar rats by streptozotocin injection and high-fat diet feeding. The rats were randomly divided into four groups: control group, diabetic group (DM), low-dose LCZ696 treatment group (LCL), and high-dose LCZ696 treatment group (LCH). LCZ696 was administered daily at a dose of 30 mg/kg or 60 mg/kg for 16 weeks. Serum N-terminal pro-brain natriuretic peptide (NT-proBNP) levels were measured and cardiac function was assessed by echocardiography. Biochemical analyses included blood glucose, serum triglycerides, cholesterol, creatinine, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and other inflammatory cytokines. Myocardial apoptosis and fibrosis were assessed by histopathologic analysis. Western blot analysis was performed to determine the expression of relevant proteins and factors in the Akt/FoxO1 signaling pathway. Results: Compared with the control group, the DM group showed significant cardiac dysfunction (left ventricular ejection fraction (LVEF) 51.7 ± 3.3 vs. 81.2 ± 1.8, p < 0.05), significantly increased levels of caspase-3 protein associated with myocardial apoptosis (p < 0.05), significantly decreased levels of B-cell lymphoma 2 (Bcl-2) expression (p < 0.05), and alterations in cardiac structure. Treatment with LCZ696 effectively improved cardiac function in diabetes mellitus rats (LVEF improved from 51.7 ± 3.3 in DM group to 62.5 ± 4.1 in DM+LCL group, p < 0.05; and to 75.6 ± 4.8 in DM+LCH group, p < 0.05), significantly downregulated caspase-3 protein expression related to myocardial apoptosis (p < 0.05), and significantly upregulated Bcl-2 expression (p < 0.05), with a more pronounced effect observed with high-dose LCZ696 treatment. Furthermore, LCZ696 treatment activated the Akt/FoxO1 signaling pathway, and inhibited myocardial inflammation (downregulated TNF-α and IL-6 expressions, p < 0.05). Conclusions: LCZ696 can protect the myocardium from damage and ameliorate cardiac function in a rat model of diabetic heart disease. These findings suggest that LCZ696 could be a potential therapeutic agent for DCM.