Dataset Information

Vasopressin type 1A receptor deletion enhances cardiac contractility, ?-adrenergic receptor sensitivity and acute cardiac injury-induced dysfunction.

ABSTRACT: Vasopressin type 1A receptor (V1AR) expression is elevated in chronic human heart failure (HF) and contributes to cardiac dysfunction in animal models, in part via reduced ?-adrenergic receptor (?AR) responsiveness. Although cardiac V1AR overexpression and V1AR stimulation are each sufficient to decrease ?AR activity, it is unknown whether V1AR inhibition conversely augments ?AR responsiveness. Further, although V1AR has been shown to contribute to chronic progression of HF, its impact on cardiac function following acute ischaemic injury has not been reported. Using V1AR knockout (V1AR KO) mice we assessed the impact of V1AR deletion on cardiac contractility at baseline and following ischaemic injury, ?AR sensitivity and cardiomyocyte responsiveness to ?AR stimulation. Strikingly, baseline cardiac contractility was enhanced in V1AR KO mice and they experienced a greater loss in contractile function than control mice following acute ischaemic injury, although the absolute levels of cardiac dysfunction and survival rates did not differ. Enhanced cardiac contractility in V1AR KO mice was associated with augmented ?-blocker sensitivity, suggesting increased basal ?AR activity, and indeed levels of left ventricular cAMP, as well as phospholamban (PLB) and cardiac troponin I (cTnI) phosphorylation were elevated compared with control mice. At the cellular level, myocytes isolated from V1AR KO mice demonstrated increased responsiveness to ?AR stimulation consistent with the finding that acute pharmacological V1AR inhibition enhanced ?AR-mediated contractility in control myocytes. Therefore, although V1AR deletion does not protect the heart from the rapid development of cardiac dysfunction following acute ischaemic injury, its effects on ?AR activity suggest that acute V1AR inhibition could be utilized to promote myocyte contractile performance.

SUBMITTER: Wasilewski MA

PROVIDER: S-EPMC5334456 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Vasopressin type 1A receptor deletion enhances cardiac contractility, β-adrenergic receptor sensitivity and acute cardiac injury-induced dysfunction.

Wasilewski Melissa A MA Grisanti Laurel A LA Song Jianliang J Carter Rhonda L RL Repas Ashley A AA Myers Valerie D VD Gao Erhe E Koch Walter J WJ Cheung Joseph Y JY Feldman Arthur M AM Tilley Douglas G DG

Clinical science (London, England : 1979) 20160902 22

Vasopressin type 1A receptor (V1AR) expression is elevated in chronic human heart failure (HF) and contributes to cardiac dysfunction in animal models, in part via reduced β-adrenergic receptor (βAR) responsiveness. Although cardiac V1AR overexpression and V1AR stimulation are each sufficient to decrease βAR activity, it is unknown whether V1AR inhibition conversely augments βAR responsiveness. Further, although V1AR has been shown to contribute to chronic progression of HF, its impact on cardia ...[more]

PMID: 27589993

Similar Datasets

Project description:AimsTo determine the mechanisms by which the ?1A-adrenergic receptor (AR) regulates cardiac contractility.BackgroundWe 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.MethodsContractility, 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.ResultsHypercontractility 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.ConclusionsWe report for the first time pleiotropic ?1A-AR signaling and the physiological role of RhoA/ROCK signaling in maintaining contractility in the normal heart.

Dataset Information

Vasopressin type 1A receptor deletion enhances cardiac contractility, ?-adrenergic receptor sensitivity and acute cardiac injury-induced dysfunction.

Publications

Vasopressin type 1A receptor deletion enhances cardiac contractility, β-adrenergic receptor sensitivity and acute cardiac injury-induced dysfunction.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets