SHANK3 Co-ordinately Regulates Autophagy and Apoptosis in Myocardial Infarction.

Wanrong Man,Gaoli Wei,Mingming Zhang,Bo Wang,Congye Li,Rui Song,Dongdong Sun,Dong Sun,Jing Gu,Haichang Wang,Baolin Guo,Kaikai Hao,Zhenyu Xiong,Xiaoming Gu,Jie Lin,Liang Zhang,Jianqiang Hu

doi:10.3389/fphys.2020.01082

Wanrong Man, Gaoli Wei + Show 15 more

Open Access

https://doi.org/10.3389/fphys.2020.01082

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Abstract

Cardiac remodeling and dysfunction are responsible for the high mortality after myocardial infarction (MI). We assessed the potential for Shank3 to alleviate the post-infarction cardiac dysfunction. The experimental MI mice model was constructed by left anterior descending coronary artery ligation. Shank3 knockout aggravated cardiac dysfunction after MI, while Shank3 overexpression alleviated it. The histological examination showed that the infarct size was significantly increased in the acute phase of MI in the Shank3 knockout group, and the cardiac dysfunction of the Shank3 knockout group was even more severe than the Shank3 overexpression group, revealed by echocardiography analyses. In vitro, cultured neonatal cardiomyocytes were subjected to simulated MI. Shank3 downregulation curbed LC3 expression and autophagosome-lysosome fusion. Furthermore, Shank3 downregulation increased cardiomyocyte apoptosis. In contrast, Shank3 upregulation induced autophagy, and inhibited apoptosis under hypoxia. In vivo, western blot analysis showed decreased levels of Atg7, Beclin1, LC3-II, and Bcl-2 as well as increased expression of p62, cleaved caspase-3, and cleaved caspase-9 in the Shank3 knockout group which suffered from MI. On the other hand, it also revealed that Shank3 overexpression induced autophagy and inhibited apoptosis after MI. Shank3 may serve as a new target for improving cardiac function after MI by inducing autophagy while inhibiting apoptosis.

Highlights

Myocardial infarction (MI) remains a big challenge (Likosky et al, 2018)
In cardiomyocytes transduced with HBAD-mRFP-GFP-LC3, Ad-sh-Shank3 transfection decreased green puncta number as compared with the control group under normal or hypoxia condition (Figure 2G)
In cardiomyocytes transduced with HBAD-mRFP-GFP-LC3, Shank3 overexpression significantly increased the number of green puncta when compared with the control group under both normal and hypoxia conditions (Figures 4G–J)

Summary

Introduction

Myocardial infarction (MI) remains a big challenge (Likosky et al, 2018). Cardiac remodeling and progressive heart failure after MI have been a major cause of mortality (Arnold et al, 2014; Bucholz et al, 2016). Many interventions have been reported to alleviate cardiac remodeling and dysfunction in animal models, the vast majority of them has proved clinically less effective against MI injury. Cardiac remodeling after MI is a complex process involving various mechanisms contributing to cardiac structural and functional injury (Prabhu and Frangogiannis, 2016; Gibb and Hill, 2018). Autophagy is a physiological and regulated process. In response to MI, increased levels of autophagy can promote cell survival (Shirakabe et al, 2016b; Sciarretta et al, 2018a). Uncontrolled apoptosis can worsen cardiac function after ischemia and hypoxia (Frangogiannis, 2015). The regulation of autophagy and apoptosis is essential for the restoration of cardiac function

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