Yu, Ze-Yan and Tan, Ju-Chiat and McMahon, Aisling C and Iismaa, Siiri E and Xiao, Xiao-Hui and Kesteven, Scott H and Reichelt, Melissa E and Mohl, Marion C and Smith, Nicola J and Fatkin, Diane and Allen, David and Head, Stewart I and Graham, Robert M and Feneley, Michael P (2014) RhoA/ROCK signaling and pleiotropic α1A-adrenergic receptor regulation of cardiac contractility. PloS One, 9 (6). pp. e99024. ISSN 1932-6203 (Gold OA)
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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.
(NHMRC grants 354400, 573732, 526622).
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 25 Jan 2016 06:18 |
| Last Modified: | 06 Jul 2016 05:32 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/229 |
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