Abstract
AimsTo determine the mechanisms by which the α1A-adrenergic receptor (AR) regulates cardiac contractility.BackgroundWe 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.MethodsContractility, calcium (Ca2+) 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.ResultsHypercontractility without hypertrophy with α1A-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, α1A-AR overexpression reduced contractility despite unchanged [Ca2+]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 Ca2+ 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.ConclusionsWe report for the first time pleiotropic α1A-AR signaling and the physiological role of RhoA/ROCK signaling in maintaining contractility in the normal heart.
Highlights
Heart failure is a major cause of death, disability and escalating health costs worldwide as populations age
Hypercontractility without hypertrophy with a1A-adrenergic receptors (ARs) 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
The hypocontractility is a pleiotropic signaling effect of the a1A-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, reducing the Ca2+ sensitivity of the contractile machinery: all these effects were rapidly reversed by selective a1A-AR blockade
Summary
Heart failure is a major cause of death, disability and escalating health costs worldwide as populations age. BARs are downregulated and uncoupled from G proteins, and a1ARs may act to maintain contractility. We reported previously that transgenic mice with cardiacrestricted a1A-AR overexpression (a1A-TG) display hypercontractility that is proportional to receptor number, is inhibited by selective a1A-AR blockade, and is not due to b-AR cross-talk [1]. This hypercontractility is not associated with cardiac hypertrophy [1,2]. We reported previously that transgenic mice with cardiac-restricted a1A-AR overexpression (a1A-TG) exhibit enhanced contractility but not hypertrophy, despite evidence implicating this Gaq/11-coupled receptor in hypertrophy
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