Rho-family GTPase 1 (Rnd1) is a biomechanical stress-sensitive activator of cardiomyocyte hypertrophy.

Abstract

Cardiac remodeling is induced by mechanical or humoral stress causing pathological changes to the heart. Here, we aimed at identifying the role of differentially regulated genes upon dynamic mechanical stretch. Microarray of dynamic stretch induced neonatal rat ventricular cardiomyocytes (NRVCMs) discovered Rho family GTPase 1 (Rnd1) as one of the significantly upregulated genes, a cardiac role of which is not known yet. Rnd1 was consistently upregulated in NRVCMs after dynamic stretch or phenylephrine (PE) stimulation, and in a mouse model of pressure overload. Overexpression of Rnd1 in NRVCMs activated the fetal gene program (including nppa and nppb) effected into a significant increase in cell surface area in untreated, stretched or PE-treated cells. Furthermore, Rnd1 overexpression showed a positive effect on cell proliferation as detected by significant increase in Ki67, Phosphohistone H3, and EdU positive NRVCMs. Through a Yeast two-hybrid screen and immunoprecipitation analysis, we identified Myozap, an intercalated disc protein, as novel interaction partner of Rnd1. Importantly, functional analysis of this interaction revealed the importance of RND1 in the RhoA and Myozap protein network that activates serum-response factor (SRF) signaling. In summary, we identified Rnd1 as a novel stretch-sensitive gene which influences cell proliferation and cellular hypertrophy via activation of RhoA-mediated SRF dependent and independent signaling pathways.

• Authors: Annika Kluge, Ashraf Yusuf Rangrez, Lucia Sophie Kilian, Jost Pott, Alexander Bernt, Robert Frauen, Astrid Rohrbeck, Norbert Frey, Derk Frank
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 129 Pg. 130-143 (04 2019) ISSN: 1095-8584 [Electronic] England
• PMID: 30797814 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019. Published by Elsevier Ltd.

Chemical References

• Intracellular Signaling Peptides and Proteins
• Rnd1 protein, rat
• Serum Response Factor
• rho GTP-Binding Proteins
• rhoA GTP-Binding Protein

Topics

• Animals
• Animals, Newborn
• Biomechanical Phenomena
• Cardiomegaly (metabolism)
• Cell Cycle
• Cell Proliferation
• Intracellular Signaling Peptides and Proteins (metabolism)
• Models, Biological
• Myocytes, Cardiac (metabolism, pathology)
• Protein Binding
• Rats, Wistar
• Serum Response Factor (metabolism)
• Signal Transduction
• Stress, Physiological
• rho GTP-Binding Proteins (metabolism)
• rhoA GTP-Binding Protein (metabolism)