In humans, Congenital heart disease (CHD) is the most common birth defect and is present in 40% of newborns affected by Down syndrome (DS). SH3 domain-binding glutamic acid-rich (SH3BGR) gene, which maps to the Down syndrome region, belongs to a gene family that is composed of SH3BGR, SH3BGRL, SH3BGRL2, and SH3BGRL3 encoding a cluster of small thioredoxin-like proteins and shares a Src homology 3 (SH3) domain. Moreover, its expression is confined to the cardiac and skeletal muscle. It is thus a potential candidate for the pathogenesis of congenital heart disease. However, biological functions of SH3BGR are yet poorly understood in the heart.

We observed a significant upregulation of SH3BGR in the hearts of mice that underwent transverse aortic constriction. Along these lines, overexpression of SH3BGR exhibited significant increase in the expression levels of hypertrophic markers Nppa and Nppb followed by increased cell surface area in neonatal rat ventricular cardiomyocytes (NRVCMs). In contrast, SH3BGR knockdown resulted in significant downregulation of these markers (Nppa- p <0.0001, n = 3, Nppb- p <0.001, n = 3, Rcan-p <0.001, n = 3). Mechanistically, using serum response factor (SRF) response element-driven luciferase activity assays with the overexpression or knockdown of SH3BGR in the presence or the absence of RhoA or its inhibitor C3-transferase, we found that the prohypertrophic effects of SH3BGR are RhoA-SRF mediated.

Further, as recent reports suggested SRF crosstalk with Hippo signaling pathway and YAP is reported to interact with Src domains of proteins, we observed significant downregulation of pLATS1 thereby increasing YAP levels on knockdown of SH3BGR suggesting nuclear import of YAP and further probable activation of pro- apoptotic genes. Moreover, cleavage of executory caspases 3 and 7 was upregulated inducing apoptosis after SH3BGR knockdown (p <0.001, n = 3). This was supplemented by cell viability assay where cells were less viable on SH3BGR knockdown.

Taken together, we here show that SH3BGR is important in maintaining cytoskeletal integrity and cellular viability of NRVCMs through modulation of SRF / YAP signaling pathways. Further in vivo studies are needed to explore if and how these findings could be involved in CHD in DS patients.