Cardiac Overexpression of XIN Prevents Dilated Cardiomyopathy Caused by TNNT2 ΔK210 Mutation.

Bin Li,Yongkun Zhan,Qianqian Liang,Xinyan Zhou,Ning Sun,Yongbo Li,Chao Zhao,Yifan Guo,Chen Xu

doi:10.3389/fcell.2021.691749

Abstract

TNNT2 mutation is associated with a range of cardiac diseases, including dilated cardiomyopathy (DCM). However, the mechanisms underlying the development of DCM and heart failure remain incompletely understood. In the present study, we found the expression of cardiac XIN protein was reduced in TNNT2-ΔK210 hESCs-derived cardiomyocytes and mouse heart tissues. We further investigated whether XIN protects against TNNT2 mutation-induced DCM. Overexpression of the repeat-containing isoform XINB decreased the percentage of myofilaments disorganization and increased cell contractility of TNNT2-ΔK210 cardiomyocytes. Moreover, overexpression of XINB by heart-specific delivery via AAV9 ameliorates DCM remodeling caused by TNNT2-ΔK210 mutation in mice, revealed by partially reversed cardiac dilation, systolic dysfunction and heart fibrosis. These results suggest that deficiency of XIN may play a critical role in the development of DCM. Consequently, our findings may provide a new mechanistic insight and represent a therapeutic target for the treatment of idiopathic DCM.

Highlights

Heart failure due to cardiomyopathy is among the most common causes of cardiovascular mortality (Harmon et al, 2005)
Deletion of lysine 210 ( K210) in TNNT2 gene has been found to cause familial dilated cardiomyopathy (DCM) (Kamisago et al, 2000), which is characterized by dilated ventricular chamber and reduced systolic function leading to progressive heart failure with high mortality (Du et al, 2007; Kimura, 2010; Sfichi-Duke et al, 2010)
We characterized that the cellular phenotypes of TNNT2- K210 hESC-CMs recapitulated DCM disease features (Li et al, 2021)

Summary

Introduction

Heart failure due to cardiomyopathy is among the most common causes of cardiovascular mortality (Harmon et al, 2005). Deletion of lysine 210 ( K210) in TNNT2 gene has been found to cause familial dilated cardiomyopathy (DCM) (Kamisago et al, 2000), which is characterized by dilated ventricular chamber and reduced systolic function leading to progressive heart failure with high mortality (Du et al, 2007; Kimura, 2010; Sfichi-Duke et al, 2010). Attempts to elucidate the molecular mechanisms underlying DCM mutations showed multiple molecular mechanisms including Ca2+ sensitivity of myofilament (Morimoto et al, 2002; Sfichi-Duke et al, 2010), remodeled intracellular calcium handling (Inoue et al, 2013; Lan et al, 2013) or interactions among the thin filaments protein constituents Combined with human pluripotent stem cell (hPSC) technology and efficient cardiac differentiation protocols, human cardiomyocytes with corresponding gene mutations could be obtain in vitro, making it possible to expediently explore the effects of genetic mutations in the initial phases of disease development using isogenic human disease model systems (Sallam et al, 2014; Savla et al, 2014)

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Conclusion