SH3-Binding Glutamic Acid Rich-Deficiency Augments Apoptosis in Neonatal Rat Cardiomyocytes.

Anushka Deshpande,Norbert Frey,Ashraf Yusuf Rangrez,Derk Frank,Ankush Borlepawar,Alexandra Rosskopf

doi:10.3390/ijms222011042

Abstract

Congenital heart disease (CHD) is one of the most common birth defects in humans, present in around 40% of newborns with Down’s syndrome (DS). The SH3 domain-binding glutamic acid-rich (SH3BGR) gene, which maps to the DS region, belongs to a gene family encoding a cluster of small thioredoxin-like proteins sharing SH3 domains. Although its expression is confined to the cardiac and skeletal muscle, the physiological role of SH3BGR in the heart is poorly understood. Interestingly, we observed a significant upregulation of SH3BGR in failing hearts of mice and human patients with hypertrophic cardiomyopathy. Along these lines, the overexpression of SH3BGR exhibited a significant increase in the expression of hypertrophic markers (Nppa and Nppb) and increased cell surface area in neonatal rat ventricular cardiomyocytes (NRVCMs), whereas its knockdown attenuated cellular hypertrophy. Mechanistically, using serum response factor (SRF) response element-driven luciferase assays in the presence or the absence of RhoA or its inhibitor, we found that the pro-hypertrophic effects of SH3BGR are mediated via the RhoA–SRF axis. Furthermore, SH3BGR knockdown resulted in the induction of apoptosis and reduced cell viability in NRVCMs via apoptotic Hippo–YAP signaling. Taking these results together, we here show that SH3BGR is vital for maintaining cytoskeletal integrity and cellular viability in NRVCMs through its modulation of the SRF/YAP signaling pathways.

Highlights

Trisomy 21, the presence of a supernumerary chromosome 21, results in one of the most common chromosomal abnormalities in humans commonly known as Down’s syndrome, occurring in about 1 in 1000 babies born each year [1]
Src homology 3 (SH3) domain-binding glutamic acid-rich (SH3BGR) Is Confined to Striated Muscle and Upregulated in Cardiac Hypertrophy
SH3BGR was first reported in association with the critical region for Down’s syndrome on chromosome 21 [23,26]

Summary

Introduction

Trisomy 21, the presence of a supernumerary chromosome 21, results in one of the most common chromosomal abnormalities in humans commonly known as Down’s syndrome, occurring in about 1 in 1000 babies born each year [1]. DS is among the most genetically complex conditions that are surprisingly compatible with human survival [2]. DS is one of the commonest disorders with a huge medical and social cost burden and is associated with several phenotypes, including congenital heart defects, leukemia, Alzheimer’s disease, Hirschsprung disease, etc. It is still unclear how and why the individuals that are affected by DS display variable phenotypes

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