Genetic Catalytic Inactivation of GRK5 Impairs Cardiac Function in Mice Via Dysregulated P53 Levels

Federica Marzano; Daniela Liccardo; Andrea Elia; Ines Mucio; Claudio de Lucia; Anna Maria Lucchese; Erhe Gao; Nicola Ferrara; Antonio Rapacciuolo; Nazareno Paolocci; Giuseppe Rengo; Walter J. Koch; Alessandro Cannavo

doi:10.1016/j.jacbts.2022.01.001

Genetic Catalytic Inactivation of GRK5 Impairs Cardiac Function in Mice Via Dysregulated P53 Levels

Federica Marzano, Daniela Liccardo, Andrea Elia, Ines Mucio, Claudio de Lucia, Anna Maria Lucchese, Erhe Gao, Nicola Ferrara, Antonio Rapacciuolo, Nazareno Paolocci, Giuseppe Rengo, Walter J. Koch, Alessandro Cannavo

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

GRK5’s catalytic activity in regulating basal and stressed cardiac function has not been studied. Herein, we studied knock-in mice in which GRK5 was mutated to render it catalytically inactive (K215R). At baseline, GRK5-K215R mice showed a marked decline in cardiac function with increased apoptosis and fibrosis. In vitro, restriction of GRK5 inside the nucleus of cardiomyocytes resulted in enhanced cell death along with higher p53 levels. Moreover, in fibroblasts, we demonstrated that K215R mutation promoted the transition into myofibroblast phenotype. This study provides novel insight into the biological actions of GRK5, that are essential for its future targeting.

Original language	English (US)
Pages (from-to)	366-380
Number of pages	15
Journal	JACC: Basic to Translational Science
Volume	7
Issue number	4
DOIs	https://doi.org/10.1016/j.jacbts.2022.01.001
State	Published - Apr 2022

Keywords

DNA
GRK
apoptosis
cardiac
nuclear

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

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10.1016/j.jacbts.2022.01.001

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Marzano, F., Liccardo, D., Elia, A., Mucio, I., de Lucia, C., Lucchese, A. M., Gao, E., Ferrara, N., Rapacciuolo, A., Paolocci, N., Rengo, G., Koch, W. J., & Cannavo, A. (2022). Genetic Catalytic Inactivation of GRK5 Impairs Cardiac Function in Mice Via Dysregulated P53 Levels. JACC: Basic to Translational Science, 7(4), 366-380. https://doi.org/10.1016/j.jacbts.2022.01.001

Marzano, F, Liccardo, D, Elia, A, Mucio, I, de Lucia, C, Lucchese, AM, Gao, E, Ferrara, N, Rapacciuolo, A, Paolocci, N, Rengo, G, Koch, WJ & Cannavo, A 2022, 'Genetic Catalytic Inactivation of GRK5 Impairs Cardiac Function in Mice Via Dysregulated P53 Levels', JACC: Basic to Translational Science, vol. 7, no. 4, pp. 366-380. https://doi.org/10.1016/j.jacbts.2022.01.001

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title = "Genetic Catalytic Inactivation of GRK5 Impairs Cardiac Function in Mice Via Dysregulated P53 Levels",

abstract = "GRK5{\textquoteright}s catalytic activity in regulating basal and stressed cardiac function has not been studied. Herein, we studied knock-in mice in which GRK5 was mutated to render it catalytically inactive (K215R). At baseline, GRK5-K215R mice showed a marked decline in cardiac function with increased apoptosis and fibrosis. In vitro, restriction of GRK5 inside the nucleus of cardiomyocytes resulted in enhanced cell death along with higher p53 levels. Moreover, in fibroblasts, we demonstrated that K215R mutation promoted the transition into myofibroblast phenotype. This study provides novel insight into the biological actions of GRK5, that are essential for its future targeting.",

keywords = "DNA, GRK, apoptosis, cardiac, nuclear",

author = "Federica Marzano and Daniela Liccardo and Andrea Elia and Ines Mucio and {de Lucia}, Claudio and Lucchese, {Anna Maria} and Erhe Gao and Nicola Ferrara and Antonio Rapacciuolo and Nazareno Paolocci and Giuseppe Rengo and Koch, {Walter J.} and Alessandro Cannavo",

note = "Funding Information: This research was funded by Italian Ministry of Education, Universities and Research “Rita Levi Montalcini 2016” (to Dr Cannavo). The research was also supported by National Institutes of Health grant P01 HL174841 (to Dr Koch), and American Heart Association (Postdoctoral fellowship 17POST33660942 to Dr Lucia). Dr Marzano was supported by a research grant provided by the CardioPaTh PhD program and she was also supported by UniNA and Compagnia San Paolo, in the frame of Programme STAR PLUS. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = apr,

doi = "10.1016/j.jacbts.2022.01.001",

language = "English (US)",

volume = "7",

pages = "366--380",

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T1 - Genetic Catalytic Inactivation of GRK5 Impairs Cardiac Function in Mice Via Dysregulated P53 Levels

AU - Marzano, Federica

AU - Liccardo, Daniela

AU - Elia, Andrea

AU - Mucio, Ines

AU - de Lucia, Claudio

AU - Lucchese, Anna Maria

AU - Gao, Erhe

AU - Ferrara, Nicola

AU - Rapacciuolo, Antonio

AU - Paolocci, Nazareno

AU - Rengo, Giuseppe

AU - Koch, Walter J.

AU - Cannavo, Alessandro

N1 - Funding Information: This research was funded by Italian Ministry of Education, Universities and Research “Rita Levi Montalcini 2016” (to Dr Cannavo). The research was also supported by National Institutes of Health grant P01 HL174841 (to Dr Koch), and American Heart Association (Postdoctoral fellowship 17POST33660942 to Dr Lucia). Dr Marzano was supported by a research grant provided by the CardioPaTh PhD program and she was also supported by UniNA and Compagnia San Paolo, in the frame of Programme STAR PLUS. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Publisher Copyright: © 2022 The Authors

PY - 2022/4

Y1 - 2022/4

N2 - GRK5’s catalytic activity in regulating basal and stressed cardiac function has not been studied. Herein, we studied knock-in mice in which GRK5 was mutated to render it catalytically inactive (K215R). At baseline, GRK5-K215R mice showed a marked decline in cardiac function with increased apoptosis and fibrosis. In vitro, restriction of GRK5 inside the nucleus of cardiomyocytes resulted in enhanced cell death along with higher p53 levels. Moreover, in fibroblasts, we demonstrated that K215R mutation promoted the transition into myofibroblast phenotype. This study provides novel insight into the biological actions of GRK5, that are essential for its future targeting.

AB - GRK5’s catalytic activity in regulating basal and stressed cardiac function has not been studied. Herein, we studied knock-in mice in which GRK5 was mutated to render it catalytically inactive (K215R). At baseline, GRK5-K215R mice showed a marked decline in cardiac function with increased apoptosis and fibrosis. In vitro, restriction of GRK5 inside the nucleus of cardiomyocytes resulted in enhanced cell death along with higher p53 levels. Moreover, in fibroblasts, we demonstrated that K215R mutation promoted the transition into myofibroblast phenotype. This study provides novel insight into the biological actions of GRK5, that are essential for its future targeting.

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Genetic Catalytic Inactivation of GRK5 Impairs Cardiac Function in Mice Via Dysregulated P53 Levels

Abstract

Keywords

ASJC Scopus subject areas

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