An Adult Mouse Model of Dilated Cardiomyopathy Caused by Inducible Cardiac-Specific Bis Deletion.

Hye Hyeon Yun,Hun Jun Park,Kyunghyun Yoo,Ho Joong Youn,Bong Woo Park,Jeong Hwa Lee,Jiyoung Yeo,Soon Young Jung,Ji Seung Ko,Hong Lim Kim

doi:10.3390/ijms22031343

Abstract

BCL-2 interacting cell death suppressor (BIS) is a multifunctional protein that has been implicated in cancer and myopathy. Various mutations of the BIS gene have been identified as causative of cardiac dysfunction in some dilated cardiomyopathy (DCM) patients. This was recently verified in cardiac-specific knock-out (KO) mice. In this study, we developed tamoxifen-inducible cardiomyocyte-specific BIS-KO (Bis-iCKO) mice to assess the role of BIS in the adult heart using the Cre-loxP strategy. The disruption of the Bis gene led to impaired ventricular function and subsequent heart failure due to DCM, characterized by reduced left ventricular contractility and dilatation that were observed using serial echocardiography and histology. The development of DCM was confirmed by alterations in Z-disk integrity and increased expression of several mRNAs associated with heart failure and remodeling. Furthermore, aggregation of desmin was correlated with loss of small heat shock protein in the Bis-iCKO mice, indicating that BIS plays an essential role in the quality control of cardiac proteins, as has been suggested in constitutive cardiac-specific KO mice. Our cardiac-specific BIS-KO mice may be a useful model for developing therapeutic interventions for DCM, especially late-onset DCM, based on the distinct phenotypes and rapid progressions.

Highlights

Bcl-2 interacting cell suppressor (BIS), called BAG3, has been identified as an anti-apoptotic protein [1]
Inducible deletion of cardiac Bis was achieved by activating cardiomyocytespecific Cre recombinase with tamoxifen injections (Figure 1A)
While a dramatic decrease in BIS levels was observed in Bis-iCKO mice, tamoxifen did not appear to affect BIS levels in the cardiomyocytes or skeletal muscles in the control mice (Bisf/f mice lacking the Cre recombinase), indicating the specificity of the α-myosin heavy chain (α-MHC)-MerCreMer system

Summary

Introduction

Bcl-2 interacting cell suppressor (BIS), called BAG3, has been identified as an anti-apoptotic protein [1]. BIS exerts a critical role in muscle integrity, based on the occurrence of mutations in the BIS gene in some fulminant myopathy (MFM) and dilated cardiomyopathy (DCM) patients [3,4]. The substitution of leucine for proline at position 209 (P209L) in exon 3 of BIS is the major pathogenic genotype of the BIS gene associated with MFM featuring progressive muscle weakness, respiratory insufficiency, and cardiac dilatation. Genome-wide epidemiological investigations have shown that more diverse mutations, including missense, nonsense, and deletion mutations, throughout exons 2 to 4 of BIS are associated with a variety of cardiovascular phenotypes in familial and non-familial DCM [3,5]. BIS levels in the heart are significantly reduced in patients undergoing heart transplantation, suggesting that BIS has a critical function in the heart [6,7]

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