The protective effect of LCZ696 in coxsackievirus B3-induced acute viral myocarditis mice
Xu Jing1, Lian Hao2, Lin Yuan-Nan1
1Department of Cardiology, Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
Insights
LCZ696 improves left ventricular ejection fraction (LVEF) in acute viral myocarditis (AVMC) by inhibiting Drp1-mediated mitochondrial fission, reducing inflammation and apoptosis. This offers a potential new treatment for heart failure caused by AVMC.
Area of Science:
- Cardiology
- Molecular Biology
- Pathology
Background:
- Acute viral myocarditis (AVMC) is a significant cause of heart failure (HF) with limited targeted therapies.
- Left ventricular ejection fraction (LVEF) is a key prognostic indicator in AVMC patients.
- LCZ696 is an established HF treatment with unexplored potential in AVMC.
Purpose of the Study:
- To investigate the efficacy of LCZ696 in improving LVEF in a mouse model of AVMC.
- To elucidate the underlying mechanism of LCZ696's effects on cardiac function, inflammation, and apoptosis in AVMC.
Main Methods:
- AVMC was induced in BALB/c mice, which were then treated with LCZ696.
- Dynamin-related protein 1 (Drp1) activity was modulated using viral vectors and pharmacological inhibitors.
- Cardiac function (LVEF), Drp1 phosphorylation, inflammation, apoptosis, and mitochondrial morphology were assessed.
Main Results:
- LCZ696 significantly improved LVEF in AVMC mice, restoring it to levels comparable to sham controls.
- LCZ696 treatment attenuated Drp1 phosphorylation, reduced inflammation and apoptosis, and mitigated mitochondrial fission.
- Modulating Drp1 activity directly impacted LVEF, inflammation, and apoptosis, confirming its role in AVMC pathogenesis.
Conclusions:
- LCZ696 demonstrates a protective effect in AVMC by enhancing LVEF and reducing cardiac inflammation and apoptosis.
- The therapeutic benefits of LCZ696 in AVMC are likely mediated through the inhibition of Drp1-mediated mitochondrial fission.
- These findings suggest LCZ696 as a promising therapeutic agent for AVMC.
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.
