RhoA/ROCK signaling and pleiotropic Î±1A-adrenergic receptor regulation of cardiac contractility

Ze-Yan Yu; Ju-Chiat Tan; Aisling C. McMahon; Siiri E. Iismaa; Xiao-Hui Xiao; Scott H. Kesteven; Melissa E. Reichelt; Marion C. Mohl; Nicola J. Smith; Diane Fatkin; David Allen; Stewart I. Head; Robert M. Graham; Michael P. Feneley

doi:10.1371/journal.pone.0099024

RhoA/ROCK signaling and pleiotropic Î±1A-adrenergic receptor regulation of cardiac contractility

Ze-Yan Yu, Ju-Chiat Tan, Aisling C. McMahon, Siiri E. Iismaa, Xiao-Hui Xiao, Scott H. Kesteven, Melissa E. Reichelt, Marion C. Mohl, Nicola J. Smith, Diane Fatkin, David Allen, Stewart I. Head, Robert M. Graham, Michael P. Feneley

Western Sydney University

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

14 Citations (Scopus)

Abstract

Aims: To determine the mechanisms by which the Î±1A-adrenergic receptor (AR) regulates cardiac contractility. Background: We reported previously that transgenic mice with cardiac-restricted Î±1A-AR overexpression (Î±1A-TG) exhibit enhanced contractility but not hypertrophy, despite evidence implicating this GÎ±q/11-coupled receptor in hypertrophy. Methods: Contractility, calcium (Ca2+) kinetics and sensitivity, and contractile proteins were examined in cardiomyocytes, isolated hearts and skinned fibers from Î±1A-TG mice (170-fold overexpression) and their non-TG littermates (NTL) before and after Î±1A-AR agonist stimulation and blockade, angiotensin II (AngII), and Rho kinase (ROCK) inhibition. Results: Hypercontractility without hypertrophy with Î±1A-AR overexpression is shown to result from increased intracellular Ca2+ release in response to agonist, augmenting the systolic amplitude of the intracellular Ca2+ concentration [Ca2+]i transient without changing resting [Ca2+]i. In the absence of agonist, however, Î±1A-AR overexpression reduced contractility despite unchanged [Ca2+]i. This hypocontractility is not due to heterologous desensitization: the contractile response to AngII, acting via its GÎ±q/11-coupled receptor, was unaltered. Rather, the hypocontractility is a pleiotropic signaling effect of the Î±1A-AR in the absence of agonist, inhibiting RhoA/ROCK activity, resulting in hypophosphorylation of both myosin phosphatase targeting subunit 1 (MYPT1) and cardiac myosin light chain 2 (cMLC2), reducing the Ca2+ sensitivity of the contractile machinery: all these effects were rapidly reversed by selective Î±1A-AR blockade. Critically, ROCK inhibition in normal hearts of NTLs without Î±1A-AR overexpression caused hypophosphorylation of both MYPT1 and cMLC2, and rapidly reduced basal contractility. Conclusions: We report for the first time pleiotropic Î±1A-AR signaling and the physiological role of RhoA/ROCK signaling in maintaining contractility in the normal heart.

Original language	English
Article number	e99024
Number of pages	10
Journal	PLoS One
Volume	9
Issue number	6
DOIs	https://doi.org/10.1371/journal.pone.0099024
Publication status	Published - 2014

Open Access - Access Right Statement

© 2014 Yu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Keywords

heart failure
hypertrophy
receptors

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1371/journal.pone.0099024

Cite this

Yu, Z.-Y., Tan, J.-C., McMahon, A. C., Iismaa, S. E., Xiao, X.-H., Kesteven, S. H., Reichelt, M. E., Mohl, M. C., Smith, N. J., Fatkin, D., Allen, D., Head, S. I., Graham, R. M., & Feneley, M. P. (2014). RhoA/ROCK signaling and pleiotropic Î±1A-adrenergic receptor regulation of cardiac contractility. PLoS One, 9(6), Article e99024. https://doi.org/10.1371/journal.pone.0099024

@article{2204eb000f64474a8c050e0d68fc54f5,

title = "RhoA/ROCK signaling and pleiotropic {\^I}±1A-adrenergic receptor regulation of cardiac contractility",

abstract = "Aims: To determine the mechanisms by which the {\^I}±1A-adrenergic receptor (AR) regulates cardiac contractility. Background: We reported previously that transgenic mice with cardiac-restricted {\^I}±1A-AR overexpression ({\^I}±1A-TG) exhibit enhanced contractility but not hypertrophy, despite evidence implicating this G{\^I}±q/11-coupled receptor in hypertrophy. Methods: Contractility, calcium (Ca2+) kinetics and sensitivity, and contractile proteins were examined in cardiomyocytes, isolated hearts and skinned fibers from {\^I}±1A-TG mice (170-fold overexpression) and their non-TG littermates (NTL) before and after {\^I}±1A-AR agonist stimulation and blockade, angiotensin II (AngII), and Rho kinase (ROCK) inhibition. Results: Hypercontractility without hypertrophy with {\^I}±1A-AR overexpression is shown to result from increased intracellular Ca2+ release in response to agonist, augmenting the systolic amplitude of the intracellular Ca2+ concentration [Ca2+]i transient without changing resting [Ca2+]i. In the absence of agonist, however, {\^I}±1A-AR overexpression reduced contractility despite unchanged [Ca2+]i. This hypocontractility is not due to heterologous desensitization: the contractile response to AngII, acting via its G{\^I}±q/11-coupled receptor, was unaltered. Rather, the hypocontractility is a pleiotropic signaling effect of the {\^I}±1A-AR in the absence of agonist, inhibiting RhoA/ROCK activity, resulting in hypophosphorylation of both myosin phosphatase targeting subunit 1 (MYPT1) and cardiac myosin light chain 2 (cMLC2), reducing the Ca2+ sensitivity of the contractile machinery: all these effects were rapidly reversed by selective {\^I}±1A-AR blockade. Critically, ROCK inhibition in normal hearts of NTLs without {\^I}±1A-AR overexpression caused hypophosphorylation of both MYPT1 and cMLC2, and rapidly reduced basal contractility. Conclusions: We report for the first time pleiotropic {\^I}±1A-AR signaling and the physiological role of RhoA/ROCK signaling in maintaining contractility in the normal heart.",

keywords = "heart failure, hypertrophy, receptors",

author = "Ze-Yan Yu and Ju-Chiat Tan and McMahon, {Aisling C.} and Iismaa, {Siiri E.} and Xiao-Hui Xiao and Kesteven, {Scott H.} and Reichelt, {Melissa E.} and Mohl, {Marion C.} and Smith, {Nicola J.} and Diane Fatkin and David Allen and Head, {Stewart I.} and Graham, {Robert M.} and Feneley, {Michael P.}",

year = "2014",

doi = "10.1371/journal.pone.0099024",

language = "English",

volume = "9",

journal = "PLoS One",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "6",

}

TY - JOUR

T1 - RhoA/ROCK signaling and pleiotropic Î±1A-adrenergic receptor regulation of cardiac contractility

AU - Yu, Ze-Yan

AU - Tan, Ju-Chiat

AU - McMahon, Aisling C.

AU - Iismaa, Siiri E.

AU - Xiao, Xiao-Hui

AU - Kesteven, Scott H.

AU - Reichelt, Melissa E.

AU - Mohl, Marion C.

AU - Smith, Nicola J.

AU - Fatkin, Diane

AU - Allen, David

AU - Head, Stewart I.

AU - Graham, Robert M.

AU - Feneley, Michael P.

PY - 2014

Y1 - 2014

N2 - Aims: To determine the mechanisms by which the Î±1A-adrenergic receptor (AR) regulates cardiac contractility. Background: We reported previously that transgenic mice with cardiac-restricted Î±1A-AR overexpression (Î±1A-TG) exhibit enhanced contractility but not hypertrophy, despite evidence implicating this GÎ±q/11-coupled receptor in hypertrophy. Methods: Contractility, calcium (Ca2+) kinetics and sensitivity, and contractile proteins were examined in cardiomyocytes, isolated hearts and skinned fibers from Î±1A-TG mice (170-fold overexpression) and their non-TG littermates (NTL) before and after Î±1A-AR agonist stimulation and blockade, angiotensin II (AngII), and Rho kinase (ROCK) inhibition. Results: Hypercontractility without hypertrophy with Î±1A-AR overexpression is shown to result from increased intracellular Ca2+ release in response to agonist, augmenting the systolic amplitude of the intracellular Ca2+ concentration [Ca2+]i transient without changing resting [Ca2+]i. In the absence of agonist, however, Î±1A-AR overexpression reduced contractility despite unchanged [Ca2+]i. This hypocontractility is not due to heterologous desensitization: the contractile response to AngII, acting via its GÎ±q/11-coupled receptor, was unaltered. Rather, the hypocontractility is a pleiotropic signaling effect of the Î±1A-AR in the absence of agonist, inhibiting RhoA/ROCK activity, resulting in hypophosphorylation of both myosin phosphatase targeting subunit 1 (MYPT1) and cardiac myosin light chain 2 (cMLC2), reducing the Ca2+ sensitivity of the contractile machinery: all these effects were rapidly reversed by selective Î±1A-AR blockade. Critically, ROCK inhibition in normal hearts of NTLs without Î±1A-AR overexpression caused hypophosphorylation of both MYPT1 and cMLC2, and rapidly reduced basal contractility. Conclusions: We report for the first time pleiotropic Î±1A-AR signaling and the physiological role of RhoA/ROCK signaling in maintaining contractility in the normal heart.

AB - Aims: To determine the mechanisms by which the Î±1A-adrenergic receptor (AR) regulates cardiac contractility. Background: We reported previously that transgenic mice with cardiac-restricted Î±1A-AR overexpression (Î±1A-TG) exhibit enhanced contractility but not hypertrophy, despite evidence implicating this GÎ±q/11-coupled receptor in hypertrophy. Methods: Contractility, calcium (Ca2+) kinetics and sensitivity, and contractile proteins were examined in cardiomyocytes, isolated hearts and skinned fibers from Î±1A-TG mice (170-fold overexpression) and their non-TG littermates (NTL) before and after Î±1A-AR agonist stimulation and blockade, angiotensin II (AngII), and Rho kinase (ROCK) inhibition. Results: Hypercontractility without hypertrophy with Î±1A-AR overexpression is shown to result from increased intracellular Ca2+ release in response to agonist, augmenting the systolic amplitude of the intracellular Ca2+ concentration [Ca2+]i transient without changing resting [Ca2+]i. In the absence of agonist, however, Î±1A-AR overexpression reduced contractility despite unchanged [Ca2+]i. This hypocontractility is not due to heterologous desensitization: the contractile response to AngII, acting via its GÎ±q/11-coupled receptor, was unaltered. Rather, the hypocontractility is a pleiotropic signaling effect of the Î±1A-AR in the absence of agonist, inhibiting RhoA/ROCK activity, resulting in hypophosphorylation of both myosin phosphatase targeting subunit 1 (MYPT1) and cardiac myosin light chain 2 (cMLC2), reducing the Ca2+ sensitivity of the contractile machinery: all these effects were rapidly reversed by selective Î±1A-AR blockade. Critically, ROCK inhibition in normal hearts of NTLs without Î±1A-AR overexpression caused hypophosphorylation of both MYPT1 and cMLC2, and rapidly reduced basal contractility. Conclusions: We report for the first time pleiotropic Î±1A-AR signaling and the physiological role of RhoA/ROCK signaling in maintaining contractility in the normal heart.

KW - heart failure

KW - hypertrophy

KW - receptors

UR - http://handle.westernsydney.edu.au:8081/1959.7/uws:42203

U2 - 10.1371/journal.pone.0099024

DO - 10.1371/journal.pone.0099024

M3 - Article

SN - 1932-6203

VL - 9

JO - PLoS One

JF - PLoS One

IS - 6

M1 - e99024

ER -

RhoA/ROCK signaling and pleiotropic Î±1A-adrenergic receptor regulation of cardiac contractility

Abstract

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Keywords

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