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Title: RhoA/ROCK signaling and pleiotropic α1A-adrenergic receptor regulation of cardiac contractility.
Authors: Yu, Z. Y.
Tan, J. C.
McMahon, Aisling 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.
First Published: 11-Jun-2014
Publisher: Public Library of Science
Citation: PLoS One, 2014 9(6): e99024
Abstract: AIMS: To determine the mechanisms by which the α1A-adrenergic receptor (AR) regulates cardiac contractility. BACKGROUND: We reported previously that transgenic mice with cardiac-restricted α1A-AR overexpression (α1A-TG) exhibit enhanced contractility but not hypertrophy, despite evidence implicating this Gαq/11-coupled receptor in hypertrophy. METHODS: Contractility, calcium (Ca(2+)) kinetics and sensitivity, and contractile proteins were examined in cardiomyocytes, isolated hearts and skinned fibers from α1A-TG mice (170-fold overexpression) and their non-TG littermates (NTL) before and after α1A-AR agonist stimulation and blockade, angiotensin II (AngII), and Rho kinase (ROCK) inhibition. RESULTS: Hypercontractility without hypertrophy with α1A-AR overexpression is shown to result from increased intracellular Ca(2+) release in response to agonist, augmenting the systolic amplitude of the intracellular Ca(2+) concentration [Ca(2+)]i transient without changing resting [Ca(2+)]i. In the absence of agonist, however, α1A-AR overexpression reduced contractility despite unchanged [Ca(2+)]i. This hypocontractility is not due to heterologous desensitization: the contractile response to AngII, acting via its Gαq/11-coupled receptor, was unaltered. Rather, the hypocontractility is a pleiotropic signaling effect of the α1A-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 Ca(2+) sensitivity of the contractile machinery: all these effects were rapidly reversed by selective α1A-AR blockade. Critically, ROCK inhibition in normal hearts of NTLs without α1A-AR overexpression caused hypophosphorylation of both MYPT1 and cMLC2, and rapidly reduced basal contractility. CONCLUSIONS: We report for the first time pleiotropic α1A-AR signaling and the physiological role of RhoA/ROCK signaling in maintaining contractility in the normal heart.
DOI Link: 10.1371/journal.pone.0099024
ISSN: 1932-6203
eISSN: 1932-6203
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: © 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.
Appears in Collections:Published Articles, Dept. of Cardiovascular Sciences

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