The protective effect of LCZ696 in coxsackievirus B3‐induced acute viral myocarditis mice

AIMS: Acute viral myocarditis (AVMC) is the aetiology of heart failure (HF) with few specific treatments. The improvement of left ventricular ejection fraction (LVEF) is a critical predictor for the prognosis of AVMC. LCZ696 is a drug used in HF to improve LVEF, with a few research on AVMC. In this research, we evaluated the effects and mechanism of LCZ696 in improving LVEF in AVMC. METHODS: Eighty 4‐week‐old male BALB/c mice were randomly divided into four groups of 20: Sham; Sham + LCZ696 (60 mg/kg/d); AVMC; AVMC + LCZ696. The above experiments were repeated by CVB3‐infected HL‐1 and Mdivi‐1 to down‐regulated dynamin‐related protein 1(Drp1). Adeno‐associated virus 9 (AAV9) with enhanced green fluorescent proteins (GFP) was injected to produce Drp1‐overexpression mice and set up four groups: AVMC group, AVMC + AAV group, AVMC + LCZ696 group, and AVMC + LCZ696 + AAV group (n = 20 in each group). LVEF was evaluated by echocardiography at a similar heart rate (HR) at d7, Drp1 (p‐Drp1), inflammation and apoptosis by histology and Western blot (WB), and mitochondrial by electron microscopy. RESULTS: Cardiac function were injured in AVMC that LCZ696 reversed (LVEF, %: Sham: 68.99 ± 9.67; Sham + LCZ696: 71.96 ± 6.20; AVMC: 30.95 ± 6.40*; AVMC + LCZ696: 68.99 ± 9.67*#, *P < 0.05 vs. Sham, #P < 0.05 vs. AVMC). LCZ696 attenuated p‐Drp1 expression, inflammation, apoptosis, and mitochondrial fission (p‐Drp1/Drp1: Sham: 1; Sham + LCZ696: 1.37 ± 0.22; AVMC: 2.29 ± 0.36*; AVMC+LCZ696: 1.43 ± 0.08*#, *P < 0.05 vs. Sham, #P < 0.05 vs. AVMC). Some of the above results were repeated in CVB3‐infected HL‐1 cells and Mdivi‐1. AAV increased Drp1 expression and mitochondrial fission, inflammatory, and apoptosis. Compared with the AVMC + AAV group, the LVEF increased from 24.44 ± 0.03% to 32.33 ± 0.05% in the AVMC + LCZ696 + AAV group(P < 0.05), p‐Drp1/Drp1 decreased from 0.54 ± 0.12 to 0.42 ± 0.09*, and IL‐6, c‐IL‐1β, and c‐caspase‐3/caspase‐3 decreased from 1.07 ± 0.22 to 0.72 ± 0.08*, from 1.03 ± 0.14 to 0.79 ± 0.09*, and from 4.69 ± 0.29 to 0.92 ± 0.13*, respectively (*P < 0.05). CONCLUSIONS: LCZ696 has a protective effect on AVMC by improving LVEF and reducing inflammation and apoptosis, which may be due to the inhibition of Drp1‐mediated mitochondrial fission.