SH3-Binding Glutamic Acid Rich-Deficiency Augments Apoptosis in Neonatal Rat Cardiomyocytes
Anushka Deshpande1,2,3, Ankush Borlepawar1,3, Alexandra Rosskopf1
1Department of Internal Medicine III, Cardiology and Angiology, University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
Insights
The SH3 domain-binding glutamic acid-rich (SH3BGR) gene promotes heart cell growth and survival. Its dysregulation is linked to heart failure and hypertrophic cardiomyopathy, highlighting its crucial role in cardiac health.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Genetics of Congenital Heart Disease
Background:
- Congenital heart disease (CHD) is a common birth defect, particularly in Down's syndrome (DS).
- The SH3 domain-binding glutamic acid-rich (SH3BGR) gene, located in the DS region, has an unclear role in heart physiology despite muscle-specific expression.
- SH3BGR is upregulated in failing hearts and hypertrophic cardiomyopathy.
Purpose of the Study:
- To investigate the physiological role of SH3BGR in cardiac cells.
- To elucidate the molecular mechanisms underlying SH3BGR's effects on cardiac hypertrophy and viability.
Main Methods:
- Overexpression and knockdown of SH3BGR in neonatal rat ventricular cardiomyocytes (NRVCMs).
- Analysis of hypertrophic markers (Nppa, Nppb) and cell surface area.
- Luciferase assays to assess the RhoA-SRF signaling pathway.
- Investigation of Hippo-YAP signaling in response to SH3BGR modulation.
Main Results:
- SH3BGR overexpression increased hypertrophic markers and cell size in NRVCMs.
- SH3BGR knockdown attenuated cardiac hypertrophy.
- SH3BGR's pro-hypertrophic effects are mediated by the RhoA-SRF axis.
- SH3BGR knockdown induced apoptosis and reduced cell viability via the Hippo-YAP pathway.
Conclusions:
- SH3BGR plays a critical role in maintaining cardiac cell viability and cytoskeletal integrity.
- SH3BGR modulates SRF and YAP signaling pathways, impacting cardiac hypertrophy and apoptosis.
- Understanding SH3BGR's function offers potential insights into treating heart conditions like hypertrophic cardiomyopathy.
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.
