Evidence map›Paper›PMID 24919197›Full record

ArticlePloS one2014

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 and 4 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
1.0field-weighted citation impact, top 26% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

8 citing papers in PubMed, 15 citations in OpenAlex.

  1. Article
  2. Review
  3. Targeting Adrenergic Receptors in Metabolic Therapies for Heart Failure.International journal of molecular sciences · 2021
    Review
  4. Article
  5. Article
  6. Review
  7. Article
  8. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors at 4 institutions in 1 country.

Ze-Yan YuVictor Chang Cardiac Research Institute, Darlinghurst, Australia; Cardiology Department, St Vincent's Hospital, Darlinghurst, Australia; Faculty of Medicine, University of New South Wales, Sydney, Australia.
Ju-Chiat TanVictor Chang Cardiac Research Institute, Darlinghurst, Australia.
Aisling C McMahonVictor Chang Cardiac Research Institute, Darlinghurst, Australia; Cardiology Department, St Vincent's Hospital, Darlinghurst, Australia.
Siiri E IismaaVictor Chang Cardiac Research Institute, Darlinghurst, Australia; Faculty of Medicine, University of New South Wales, Sydney, Australia.
Xiao-Hui XiaoVictor Chang Cardiac Research Institute, Darlinghurst, Australia.
Scott H KestevenVictor Chang Cardiac Research Institute, Darlinghurst, Australia.
Melissa E ReicheltVictor Chang Cardiac Research Institute, Darlinghurst, Australia.
Marion C MohlVictor Chang Cardiac Research Institute, Darlinghurst, Australia.
Nicola J SmithVictor Chang Cardiac Research Institute, Darlinghurst, Australia; Faculty of Medicine, University of New South Wales, Sydney, Australia.
Diane FatkinVictor Chang Cardiac Research Institute, Darlinghurst, Australia; Cardiology Department, St Vincent's Hospital, Darlinghurst, Australia; Faculty of Medicine, University of New South Wales, Sydney, Australia.
David AllenPhysiology Department, University of Sydney, Sydney, Australia.
Stewart I HeadPhysiology Department, University of New South Wales, Sydney, Australia.
Robert M GrahamVictor Chang Cardiac Research Institute, Darlinghurst, Australia; Cardiology Department, St Vincent's Hospital, Darlinghurst, Australia; Faculty of Medicine, University of New South Wales, Sydney, Australia.
Michael P FeneleyVictor Chang Cardiac Research Institute, Darlinghurst, Australia; Cardiology Department, St Vincent's Hospital, Darlinghurst, Australia; Faculty of Medicine, University of New South Wales, Sydney, Australia.
Victor Chang Cardiac Research Institute · AUSt Vincent's Hospital Sydney · AUUNSW Sydney · AUUniversity of Sydney · AU

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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 (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.

resultsHypercontractility 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.

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.

Indexed as

Signal TransductionAdrenergic alpha-AgonistsAnimalsCalciumMiceMice, TransgenicMyocardial ContractionPhosphorylationReceptors, Adrenergic, alpha-1rhoA GTP-Binding Proteinrho-Associated KinasesAdrenergic alpha-AgonistsCalciumReceptors, Adrenergic, alpha-1rhoA GTP-Binding Proteinrho-Associated KinasesRock1 protein, mouse

Identifiers

PMID24919197
PMCPMC4053326
OpenAlexW1969713529

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.