GRK2 blockade with βaRKct is essential for cardiac β2-adrenergic receptor signaling towards increased contractility

Norma C. Salazar, Ximena Vallejos, Ashley Siryk, Giuseppe Rengo, Alessandro Cannavo, Daniela Liccardo, Claudio De Lucia, Erhe Gao, Dario Leosco, Walter J. Koch, Anastasios Lymperopoulos

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Background: β1- and β2-adrenergic receptors (ARs) play distinct roles in the heart, e.g. β1AR is pro-contractile and pro-apoptotic but β2AR anti-apoptotic and only weakly pro-contractile. G protein coupled receptor kinase (GRK)-2 desensitizes and opposes βAR pro-contractile signaling by phosphorylating the receptor and inducing beta-arrestin (βarr) binding. We posited herein that GRK2 blockade might enhance the pro-contractile signaling of the β2AR subtype in the heart. We tested the effects of cardiac-targeted GRK2 inhibition in vivo exclusively on β2AR signaling under normal conditions and in heart failure (HF). Results: We crossed β1AR knockout (B1KO) mice with cardiac-specific transgenic mice expressing the βARKct, a known GRK2 inhibitor, and studied the offspring under normal conditions and in post-myocardial infarction (MI). βARKct expression in vivo proved essential for β2AR-dependent contractile function, as β2AR stimulation with isoproterenol fails to increase contractility in either healthy or post-MI B1KO mice and it only does so in the presence of βARKct. The main underlying mechanism for this is blockade of the interaction of phosphodiesterase (PDE) type 4D with the cardiac β2AR, which is normally mediated by the actions of GRK2 and βarrs on the receptor. The molecular "brake" that PDE4D poses on β2AR signaling to contractility stimulation is thus "released". Regarding the other beneficial functions of cardiac β2AR, βARKct increased overall survival of the post-MI B1KO mice progressing to HF, via a decrease in cardiac apoptosis and an increase in wound healing-associated inflammation early (at 24 hrs) post-MI. However, these effects disappear by 4 weeks post-MI, and, in their place, upregulation of the other major GRK in the heart, GRK5, is observed. Conclusions: GRK2 inhibition in vivo with βARKct is absolutely essential for cardiac β2AR pro-contractile signaling and function. In addition, β2AR anti-apoptotic signaling in post-MI HF is augmented by βARKct, although this effect is short-lived.

Original languageEnglish
Article number64
JournalCell Communication and Signaling
Volume11
Issue number1
DOIs
Publication statusPublished - 2013

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Adrenergic Receptors
Myocardial Infarction
Heart Failure
G-Protein-Coupled Receptor Kinase 2
G-Protein-Coupled Receptor Kinases
Type 4 Cyclic Nucleotide Phosphodiesterase
Arrestin
Isoproterenol
Brakes
Knockout Mice
Wound Healing
Transgenic Mice
Up-Regulation
Apoptosis
Inflammation

Keywords

  • Cardiac β-adrenergic receptor
  • GRK2 inhibition
  • GRK5
  • Post-myocardial infarction survival
  • Pro-contractile signaling

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Biochemistry
  • Medicine(all)

Cite this

GRK2 blockade with βaRKct is essential for cardiac β2-adrenergic receptor signaling towards increased contractility. / Salazar, Norma C.; Vallejos, Ximena; Siryk, Ashley; Rengo, Giuseppe; Cannavo, Alessandro; Liccardo, Daniela; De Lucia, Claudio; Gao, Erhe; Leosco, Dario; Koch, Walter J.; Lymperopoulos, Anastasios.

In: Cell Communication and Signaling, Vol. 11, No. 1, 64, 2013.

Research output: Contribution to journalArticle

Salazar, NC, Vallejos, X, Siryk, A, Rengo, G, Cannavo, A, Liccardo, D, De Lucia, C, Gao, E, Leosco, D, Koch, WJ & Lymperopoulos, A 2013, 'GRK2 blockade with βaRKct is essential for cardiac β2-adrenergic receptor signaling towards increased contractility', Cell Communication and Signaling, vol. 11, no. 1, 64. https://doi.org/10.1186/1478-811X-11-64
Salazar, Norma C. ; Vallejos, Ximena ; Siryk, Ashley ; Rengo, Giuseppe ; Cannavo, Alessandro ; Liccardo, Daniela ; De Lucia, Claudio ; Gao, Erhe ; Leosco, Dario ; Koch, Walter J. ; Lymperopoulos, Anastasios. / GRK2 blockade with βaRKct is essential for cardiac β2-adrenergic receptor signaling towards increased contractility. In: Cell Communication and Signaling. 2013 ; Vol. 11, No. 1.
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AU - Salazar, Norma C.

AU - Vallejos, Ximena

AU - Siryk, Ashley

AU - Rengo, Giuseppe

AU - Cannavo, Alessandro

AU - Liccardo, Daniela

AU - De Lucia, Claudio

AU - Gao, Erhe

AU - Leosco, Dario

AU - Koch, Walter J.

AU - Lymperopoulos, Anastasios

PY - 2013

Y1 - 2013

N2 - Background: β1- and β2-adrenergic receptors (ARs) play distinct roles in the heart, e.g. β1AR is pro-contractile and pro-apoptotic but β2AR anti-apoptotic and only weakly pro-contractile. G protein coupled receptor kinase (GRK)-2 desensitizes and opposes βAR pro-contractile signaling by phosphorylating the receptor and inducing beta-arrestin (βarr) binding. We posited herein that GRK2 blockade might enhance the pro-contractile signaling of the β2AR subtype in the heart. We tested the effects of cardiac-targeted GRK2 inhibition in vivo exclusively on β2AR signaling under normal conditions and in heart failure (HF). Results: We crossed β1AR knockout (B1KO) mice with cardiac-specific transgenic mice expressing the βARKct, a known GRK2 inhibitor, and studied the offspring under normal conditions and in post-myocardial infarction (MI). βARKct expression in vivo proved essential for β2AR-dependent contractile function, as β2AR stimulation with isoproterenol fails to increase contractility in either healthy or post-MI B1KO mice and it only does so in the presence of βARKct. The main underlying mechanism for this is blockade of the interaction of phosphodiesterase (PDE) type 4D with the cardiac β2AR, which is normally mediated by the actions of GRK2 and βarrs on the receptor. The molecular "brake" that PDE4D poses on β2AR signaling to contractility stimulation is thus "released". Regarding the other beneficial functions of cardiac β2AR, βARKct increased overall survival of the post-MI B1KO mice progressing to HF, via a decrease in cardiac apoptosis and an increase in wound healing-associated inflammation early (at 24 hrs) post-MI. However, these effects disappear by 4 weeks post-MI, and, in their place, upregulation of the other major GRK in the heart, GRK5, is observed. Conclusions: GRK2 inhibition in vivo with βARKct is absolutely essential for cardiac β2AR pro-contractile signaling and function. In addition, β2AR anti-apoptotic signaling in post-MI HF is augmented by βARKct, although this effect is short-lived.

AB - Background: β1- and β2-adrenergic receptors (ARs) play distinct roles in the heart, e.g. β1AR is pro-contractile and pro-apoptotic but β2AR anti-apoptotic and only weakly pro-contractile. G protein coupled receptor kinase (GRK)-2 desensitizes and opposes βAR pro-contractile signaling by phosphorylating the receptor and inducing beta-arrestin (βarr) binding. We posited herein that GRK2 blockade might enhance the pro-contractile signaling of the β2AR subtype in the heart. We tested the effects of cardiac-targeted GRK2 inhibition in vivo exclusively on β2AR signaling under normal conditions and in heart failure (HF). Results: We crossed β1AR knockout (B1KO) mice with cardiac-specific transgenic mice expressing the βARKct, a known GRK2 inhibitor, and studied the offspring under normal conditions and in post-myocardial infarction (MI). βARKct expression in vivo proved essential for β2AR-dependent contractile function, as β2AR stimulation with isoproterenol fails to increase contractility in either healthy or post-MI B1KO mice and it only does so in the presence of βARKct. The main underlying mechanism for this is blockade of the interaction of phosphodiesterase (PDE) type 4D with the cardiac β2AR, which is normally mediated by the actions of GRK2 and βarrs on the receptor. The molecular "brake" that PDE4D poses on β2AR signaling to contractility stimulation is thus "released". Regarding the other beneficial functions of cardiac β2AR, βARKct increased overall survival of the post-MI B1KO mice progressing to HF, via a decrease in cardiac apoptosis and an increase in wound healing-associated inflammation early (at 24 hrs) post-MI. However, these effects disappear by 4 weeks post-MI, and, in their place, upregulation of the other major GRK in the heart, GRK5, is observed. Conclusions: GRK2 inhibition in vivo with βARKct is absolutely essential for cardiac β2AR pro-contractile signaling and function. In addition, β2AR anti-apoptotic signaling in post-MI HF is augmented by βARKct, although this effect is short-lived.

KW - Cardiac β-adrenergic receptor

KW - GRK2 inhibition

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KW - Post-myocardial infarction survival

KW - Pro-contractile signaling

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