The Amino-Terminal Domain of GRK5 Inhibits Cardiac Hypertrophy through the Regulation of Calcium-Calmodulin Dependent Transcription Factors.

Authors:
Daniela Sorriento
Daniela Sorriento
Department of Clinical Medicine
Italy
Gaetano Santulli
Gaetano Santulli
Federico II University of Naples
Italy
Michele Ciccarelli
Michele Ciccarelli
University of Salerno
Fisciano | Italy
Angela Serena Maione
Angela Serena Maione
University of Naples Federico II
Italy
Maddalena Illario
Maddalena Illario
University of Naples Federico II
Napoli | Italy
Bruno Trimarco
Bruno Trimarco
Federico II University
Napoli | Italy
Prof. Guido Iaccarino, MD, PhD
Prof. Guido Iaccarino, MD, PhD
Federico II University of Naples
Full Professor of Applied Medical Science and Technology
Cardiology
Napoli, Campania | Italy

Int J Mol Sci 2018 Mar 15;19(3). Epub 2018 Mar 15.

Dipartimento di Medicina, Chirurgia e Odontoiatria "Scuola Medica Salernitana"/DIPMED, Università degli Studi di Salerno, Via S. Allende, 84081 Baronissi (SA), Italy.

We have recently demonstrated that the amino-terminal domain of G protein coupled receptor kinase (GRK) type 5, (GRK5-NT) inhibits NFκB activity in cardiac cells leading to a significant amelioration of LVH. Since GRK5-NT is known to bind calmodulin, this study aimed to evaluate the functional role of GRK5-NT in the regulation of calcium-calmodulin-dependent transcription factors. We found that the overexpression of GRK5-NT in cardiomyoblasts significantly reduced the activation and the nuclear translocation of NFAT and its cofactor GATA-4 in response to phenylephrine (PE). These results were confirmed in vivo in spontaneously hypertensive rats (SHR), in which intramyocardial adenovirus-mediated gene transfer of GRK5-NT reduced both wall thickness and ventricular mass by modulating NFAT and GATA-4 activity. To further verify in vitro the contribution of calmodulin in linking GRK5-NT to the NFAT/GATA-4 pathway, we examined the effects of a mutant of GRK5 (GRK5-NTPB), which is not able to bind calmodulin. When compared to GRK5-NT, GRK5-NTPB did not modify PE-induced NFAT and GATA-4 activation. In conclusion, this study identifies a double effect of GRK5-NT in the inhibition of LVH that is based on the regulation of multiple transcription factors through means of different mechanisms and proposes the amino-terminal sequence of GRK5 as a useful prototype for therapeutic purposes.

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http://dx.doi.org/10.3390/ijms19030861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877722PMC
March 2018
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1 Citation
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