Dataset Information

RhoA/ROCK signaling and pleiotropic ?1A-adrenergic receptor regulation of cardiac contractility.

ABSTRACT:

Aims

To determine the mechanisms by which the ?1A-adrenergic receptor (AR) regulates cardiac contractility.

Background

We reported previously that transgenic mice with cardiac-restricted ?1A-AR overexpression (?1A-TG) exhibit enhanced contractility but not hypertrophy, despite evidence implicating this G?q/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 ?1A-TG mice (170-fold overexpression) and their non-TG littermates (NTL) before and after ?1A-AR agonist stimulation and blockade, angiotensin II (AngII), and Rho kinase (ROCK) inhibition.

Results

Hypercontractility without hypertrophy with ?1A-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, ?1A-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 G?q/11-coupled receptor, was unaltered. Rather, the hypocontractility is a pleiotropic signaling effect of the ?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 Ca(2+) sensitivity of the contractile machinery: all these effects were rapidly reversed by selective ?1A-AR blockade. Critically, ROCK inhibition in normal hearts of NTLs without ?1A-AR overexpression caused hypophosphorylation of both MYPT1 and cMLC2, and rapidly reduced basal contractility.

Conclusions

We report for the first time pleiotropic ?1A-AR signaling and the physiological role of RhoA/ROCK signaling in maintaining contractility in the normal heart.

SUBMITTER: Yu ZY

PROVIDER: S-EPMC4053326 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Publications

RhoA/ROCK signaling and pleiotropic α1A-adrenergic receptor regulation of cardiac contractility.

Yu Ze-Yan ZY Tan Ju-Chiat JC McMahon Aisling C AC Iismaa Siiri E SE Xiao Xiao-Hui XH Kesteven Scott H SH Reichelt Melissa E ME Mohl Marion C MC Smith Nicola J NJ Fatkin Diane D Allen David D Head Stewart I SI Graham Robert M RM Feneley Michael P MP

PloS one 20140611 6

<h4>Aims</h4>To determine the mechanisms by which the α1A-adrenergic receptor (AR) regulates cardiac contractility.<h4>Background</h4>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.<h4>Methods</h4>Contractility, calcium (Ca(2+)) kinetics and sensitivity, and contractile proteins were examined in cardiomyocytes, isolated h ...[more]

PMID: 24919197

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