LCZ696,an angiotensin receptor-neprilysin inhibitor,ameliorates diabetic cardiomyopathy by inhibiting inflammation,oxidative stress and apoptosis

Abstract

Diabetic cardiomyopathy, which refers to the destruction of the structure and function of the heart, is the primary cause of heart failure due to diabetes. LCZ696 is the first angiotensin receptor-neprilysin inhibitor (ARNi) to be used clinically. Our study investigated the role played by LCZ696 during diabetic cardiomyopathy and explored the potential mechanisms underlying these effects. Diabetes was induced by injecting streptozotocin intraperitoneally into mice, and the mice were then divided randomly into two groups: one group was treated with LCZ696 (60 mg/kg/d) for 16 weeks, and the other received no treatment. The H9C2 cardiomyoblast cell line was treated with LCZ696 under high-glucose (HG) conditions. The levels of apoptotic (Bax, Bcl-2 and cleaved caspase-3) and pro-inflammatory factors [nuclear factor (NF)-κB, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated kinase (MAPK)] were assessed in heart tissues from diabetic and normal mice and in H9C2 cells. The heart tissue structures and cardiac functions of diabetic mice were compared with those of normal mice, using histological and echocardiographic analyses. The results showed that LCZ696 inhibits the nuclear transfer of NF-κB and JNK/p38MAPK phosphorylation, and mitigates inflammation and apoptosis in diabetic mice and H9C2 cardiomyocytes under HG conditions. The histological and echocardiographic data showed that compared with untreated diabetic mice, diabetic mice treated with LCZ696 exhibited improved ventricular remodeling and cardiac function. LCZ696 also ameliorated oxidative stress in both vivo and vitro. In conclusion, LCZ696 improved diabetic cardiomyopathy by reducing cardiac inflammation, oxidative stress, and apoptosis.

Impact statement

Diabetic cardiomyopathy (DCM) is an important cause of heart failure in patients with diabetes, resulting in increased morbidity and mortality. LCZ696, which was studied here, is a novel drug for the treatment of heart failure. The latest research reports that LCZ696 is more effective for preventing heart failure than valsartan alone. However, little research has been performed examining the effects of LCZ696 on DCM. This study was designed to examine the role played by LCZ696 during DCM and the potential mechanisms underlying these effects, which may provide the basis for a new therapeutic strategy for DCM.