PLoS ONE (Jan 2014)

RhoA/ROCK signaling and pleiotropic α1A-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
https://doi.org/10.1371/journal.pone.0099024
Journal volume & issue
Vol. 9, no. 6
p. e99024

Abstract

Read online

To determine the mechanisms by which the α1A-adrenergic receptor (AR) regulates cardiac contractility.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.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.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.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.