TLR4 Activation Promotes the Progression of Experimental Autoimmune Myocarditis to Dilated Cardiomyopathy by Inducing Mitochondrial Dynamic Imbalance.

Bangwei Wu,Jian Li,Zhiyong Qi,Huanchun Ni,Xinyu Zhuang,Zhichao Wen,Bo Jin,Xinping Luo,Haiming Shi,Qiying Chen

doi:10.1155/2018/3181278

Abstract

Mitochondrial dynamic imbalance associates with several cardiovascular diseases. However, the role of mitochondrial dynamics in TLR4 activation-mediated dilated cardiomyopathy (DCM) progress remains unknown. A model of experimental autoimmune myocarditis (EAM) was established in BALB/c mice on which TLR4 activation by LPS-EB or TLR4 inhibition by LPS-RS was performed to induce chronic inflammation for 5 weeks. TLR4 activation promoted the transition of EAM to DCM as demonstrated by increased cardiomyocyte apoptosis, myocardial fibrosis, ventricular dilatation, and declined heart function. TLR4 inhibition mitigated the above DCM changes. Transmission electron microscope study showed that mitochondria became fragmented, also with damaged crista in ultrastructure in EAM mice. TLR4 activation aggravated the above mitochondrial aberration, and TLR4 inhibition alleviated it. The mitochondrial dynamic imbalance and damage in DCM development were mainly associated with OPA1 downregulation, which may be caused by elevated TNF-α level and ROS stress after TLR4 activation. Furthermore, OMA1/YME1L abnormal degradation was involved in the OPA1 dysfunction, and intervening OMA1/YME1L in H9C2 significantly alleviated mitochondrial fission, ultrastructure damage, and cell apoptosis induced by TNF-α and ROS. These data indicate that TLR4 activation resulted in OPA1 dysfunction, promoting mitochondrial dynamic imbalance and damage, which may involve in the progress of EAM to DCM.

Highlights

Dilated cardiomyopathy (DCM) is the most common cardiomyopathy worldwide characterized by ventricular cavity expansion and contraction function declination, which are associated with sudden cardiac death and heart failure [1]
We observed that the heart/ body weight ratio (H/B) was increased in control group compared with the sham group (5.2 ± 0.75 versus 4.1 ± 0.39, p < 0 05), and TLR4 activation showed a higher ratio in the LPS-EB group (6.2 ± 0.90 versus 5.2 ± 0.75, p < 0 05), but TLR4 inhibition resulted in a decrease in the LPS-RS group (Supplementary Figure 1C). These results indicate that TLR4 activation promoted the transition of experimental autoimmune myocarditis (EAM) to DCM by regulating cardiomyocyte apoptosis and myocardial fibrosis
The transcription level of the above cytokines in the myocardium was detected by RT-Polymerase Chain Reaction (PCR), which showed a consistent expression level as in serum (p < 0 05) (Supplementary Figure 1E). These results suggest that TLR4 activation may promote the myocardium ROS stress and upregulate the expression of inflammatory cytokines such as TNF-α, IL-1, and IL-6, which involved in the progression of EAM to DCM in mice

Summary

Introduction

Dilated cardiomyopathy (DCM) is the most common cardiomyopathy worldwide characterized by ventricular cavity expansion and contraction function declination, which are associated with sudden cardiac death and heart failure [1]. Myocarditis is characterized by pathological autoimmune response of the myocardium, even when asymptomatic, about 10–20% of patients will develop chronic disease eventually leading to DCM [2]. Numerous studies have demonstrated that TLR4 activation-mediated leucocyte infiltration in myocardium leads to cytokine secretion, oxidative stress, and protease release, which play a pivotal role in myocardial infarction, ischemia-reperfusion injury, myocarditis, and heart failure [4, 5]. TLR4 and downstreamsignaling activation showed importance for the induction of autoimmune myocarditis model [4, 6]. Activation of TLR4 on dendritic cell (DC) is required for the induction of acute myocarditis and heart failure [2, 8]. Satoh et al showed that myocardial expression of TLR4 was associated with enterovirus

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Conclusion