Evidence map›Paper›PMID 21106943›Full record

ArticleCirculation research2011

The inotropic peptide βARKct improves βAR responsiveness in normal and failing cardiomyocytes through G(βγ)-mediated L-type calcium current disinhibition.

Mirko Völkers, Christian Weidenhammer, Nicole Herzog, Gang Qiu, Kristin Spaich, Frederic V Wegner, Karsten Peppel, Oliver J Müller, Stefanie Schinkel, Joseph E Rabinowitz and 7 more

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

Article in Circulation research, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.

0numbers the graph read from it
0cells of the map it votes in
32citing papers in PubMed
4.6field-weighted citation impact, top 5% 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

32 citing papers in PubMed, 49 citations in OpenAlex.

  1. Article
  2. CITED4 gene therapy protects against maladaptive cardiac remodeling after ischemia/reperfusion injury in mice.Molecular therapy : the journal of the American Society of Gene Therapy · 2024
    Article
  3. Review
  4. Review
  5. Article
  6. βCirculation research · 2019
    Article
  7. Review
  8. Review
  9. Article
  10. Review
  11. Article
  12. Review
  13. S100A1 DNA-based Inotropic Therapy Protects Against Proarrhythmogenic Ryanodine Receptor 2 Dysfunction.Molecular therapy : the journal of the American Society of Gene Therapy · 2015
    Article
  14. Review
  15. Article
  16. Heart failure-specific changes in protein kinase signalling.Pflugers Archiv : European journal of physiology · 2014
    Review
  17. Article
  18. Article
  19. Review
  20. 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

17 authors at 1 institution in 2 countries.

Mirko Völkers *Center for Molecular and Translational Cardiology (M.V, C.W., N.H., K.S., P.M.), Department of Internal Medicine III (O.J.M, S.S., H.J.H., H.A.K.), Division of Cardiology, INF 350, University of Heidelberg, 69120 Heidelberg, Germany; Institute of Physiology and Pathophysiology (F.W., O.F.) Medical Biophysics, INF 326, University of Heidelberg, 69120 Heidelberg, Germany; George Zallie & Family Laboratory for Cardiovascular Gene Therapy (J.E.R., H.B., W.J.K.), Eugene Feiner Laboratory for Vascular Biology and Thrombosis (A.D.E.), Laboratory for Cardiac Stem Cell and Gene Therapy (G.Q., K.P., P.M.), Center for Translational Medicine, Thomas Jefferson University, 19107 Philadelphia, PA, USA.
Christian Weidenhammer *Center for Molecular and Translational Cardiology (M.V, C.W., N.H., K.S., P.M.), Department of Internal Medicine III (O.J.M, S.S., H.J.H., H.A.K.), Division of Cardiology, INF 350, University of Heidelberg, 69120 Heidelberg, Germany; Institute of Physiology and Pathophysiology (F.W., O.F.) Medical Biophysics, INF 326, University of Heidelberg, 69120 Heidelberg, Germany; George Zallie & Family Laboratory for Cardiovascular Gene Therapy (J.E.R., H.B., W.J.K.), Eugene Feiner Laboratory for Vascular Biology and Thrombosis (A.D.E.), Laboratory for Cardiac Stem Cell and Gene Therapy (G.Q., K.P., P.M.), Center for Translational Medicine, Thomas Jefferson University, 19107 Philadelphia, PA, USA.
Nicole HerzogCenter for Molecular and Translational Cardiology (M.V, C.W., N.H., K.S., P.M.), Department of Internal Medicine III (O.J.M, S.S., H.J.H., H.A.K.), Division of Cardiology, INF 350, University of Heidelberg, 69120 Heidelberg, Germany; Institute of Physiology and Pathophysiology (F.W., O.F.) Medical Biophysics, INF 326, University of Heidelberg, 69120 Heidelberg, Germany; George Zallie & Family Laboratory for Cardiovascular Gene Therapy (J.E.R., H.B., W.J.K.), Eugene Feiner Laboratory for Vascular Biology and Thrombosis (A.D.E.), Laboratory for Cardiac Stem Cell and Gene Therapy (G.Q., K.P., P.M.), Center for Translational Medicine, Thomas Jefferson University, 19107 Philadelphia, PA, USA.
Gang QiuCenter for Molecular and Translational Cardiology (M.V, C.W., N.H., K.S., P.M.), Department of Internal Medicine III (O.J.M, S.S., H.J.H., H.A.K.), Division of Cardiology, INF 350, University of Heidelberg, 69120 Heidelberg, Germany; Institute of Physiology and Pathophysiology (F.W., O.F.) Medical Biophysics, INF 326, University of Heidelberg, 69120 Heidelberg, Germany; George Zallie & Family Laboratory for Cardiovascular Gene Therapy (J.E.R., H.B., W.J.K.), Eugene Feiner Laboratory for Vascular Biology and Thrombosis (A.D.E.), Laboratory for Cardiac Stem Cell and Gene Therapy (G.Q., K.P., P.M.), Center for Translational Medicine, Thomas Jefferson University, 19107 Philadelphia, PA, USA.
Kristin SpaichCenter for Molecular and Translational Cardiology (M.V, C.W., N.H., K.S., P.M.), Department of Internal Medicine III (O.J.M, S.S., H.J.H., H.A.K.), Division of Cardiology, INF 350, University of Heidelberg, 69120 Heidelberg, Germany; Institute of Physiology and Pathophysiology (F.W., O.F.) Medical Biophysics, INF 326, University of Heidelberg, 69120 Heidelberg, Germany; George Zallie & Family Laboratory for Cardiovascular Gene Therapy (J.E.R., H.B., W.J.K.), Eugene Feiner Laboratory for Vascular Biology and Thrombosis (A.D.E.), Laboratory for Cardiac Stem Cell and Gene Therapy (G.Q., K.P., P.M.), Center for Translational Medicine, Thomas Jefferson University, 19107 Philadelphia, PA, USA.
Frederic V WegnerCenter for Molecular and Translational Cardiology (M.V, C.W., N.H., K.S., P.M.), Department of Internal Medicine III (O.J.M, S.S., H.J.H., H.A.K.), Division of Cardiology, INF 350, University of Heidelberg, 69120 Heidelberg, Germany; Institute of Physiology and Pathophysiology (F.W., O.F.) Medical Biophysics, INF 326, University of Heidelberg, 69120 Heidelberg, Germany; George Zallie & Family Laboratory for Cardiovascular Gene Therapy (J.E.R., H.B., W.J.K.), Eugene Feiner Laboratory for Vascular Biology and Thrombosis (A.D.E.), Laboratory for Cardiac Stem Cell and Gene Therapy (G.Q., K.P., P.M.), Center for Translational Medicine, Thomas Jefferson University, 19107 Philadelphia, PA, USA.
Karsten PeppelCenter for Molecular and Translational Cardiology (M.V, C.W., N.H., K.S., P.M.), Department of Internal Medicine III (O.J.M, S.S., H.J.H., H.A.K.), Division of Cardiology, INF 350, University of Heidelberg, 69120 Heidelberg, Germany; Institute of Physiology and Pathophysiology (F.W., O.F.) Medical Biophysics, INF 326, University of Heidelberg, 69120 Heidelberg, Germany; George Zallie & Family Laboratory for Cardiovascular Gene Therapy (J.E.R., H.B., W.J.K.), Eugene Feiner Laboratory for Vascular Biology and Thrombosis (A.D.E.), Laboratory for Cardiac Stem Cell and Gene Therapy (G.Q., K.P., P.M.), Center for Translational Medicine, Thomas Jefferson University, 19107 Philadelphia, PA, USA.
Oliver J MüllerCenter for Molecular and Translational Cardiology (M.V, C.W., N.H., K.S., P.M.), Department of Internal Medicine III (O.J.M, S.S., H.J.H., H.A.K.), Division of Cardiology, INF 350, University of Heidelberg, 69120 Heidelberg, Germany; Institute of Physiology and Pathophysiology (F.W., O.F.) Medical Biophysics, INF 326, University of Heidelberg, 69120 Heidelberg, Germany; George Zallie & Family Laboratory for Cardiovascular Gene Therapy (J.E.R., H.B., W.J.K.), Eugene Feiner Laboratory for Vascular Biology and Thrombosis (A.D.E.), Laboratory for Cardiac Stem Cell and Gene Therapy (G.Q., K.P., P.M.), Center for Translational Medicine, Thomas Jefferson University, 19107 Philadelphia, PA, USA.
Stefanie SchinkelCenter for Molecular and Translational Cardiology (M.V, C.W., N.H., K.S., P.M.), Department of Internal Medicine III (O.J.M, S.S., H.J.H., H.A.K.), Division of Cardiology, INF 350, University of Heidelberg, 69120 Heidelberg, Germany; Institute of Physiology and Pathophysiology (F.W., O.F.) Medical Biophysics, INF 326, University of Heidelberg, 69120 Heidelberg, Germany; George Zallie & Family Laboratory for Cardiovascular Gene Therapy (J.E.R., H.B., W.J.K.), Eugene Feiner Laboratory for Vascular Biology and Thrombosis (A.D.E.), Laboratory for Cardiac Stem Cell and Gene Therapy (G.Q., K.P., P.M.), Center for Translational Medicine, Thomas Jefferson University, 19107 Philadelphia, PA, USA.
Joseph E RabinowitzCenter for Molecular and Translational Cardiology (M.V, C.W., N.H., K.S., P.M.), Department of Internal Medicine III (O.J.M, S.S., H.J.H., H.A.K.), Division of Cardiology, INF 350, University of Heidelberg, 69120 Heidelberg, Germany; Institute of Physiology and Pathophysiology (F.W., O.F.) Medical Biophysics, INF 326, University of Heidelberg, 69120 Heidelberg, Germany; George Zallie & Family Laboratory for Cardiovascular Gene Therapy (J.E.R., H.B., W.J.K.), Eugene Feiner Laboratory for Vascular Biology and Thrombosis (A.D.E.), Laboratory for Cardiac Stem Cell and Gene Therapy (G.Q., K.P., P.M.), Center for Translational Medicine, Thomas Jefferson University, 19107 Philadelphia, PA, USA.
Hans-Jorg HippeCenter for Molecular and Translational Cardiology (M.V, C.W., N.H., K.S., P.M.), Department of Internal Medicine III (O.J.M, S.S., H.J.H., H.A.K.), Division of Cardiology, INF 350, University of Heidelberg, 69120 Heidelberg, Germany; Institute of Physiology and Pathophysiology (F.W., O.F.) Medical Biophysics, INF 326, University of Heidelberg, 69120 Heidelberg, Germany; George Zallie & Family Laboratory for Cardiovascular Gene Therapy (J.E.R., H.B., W.J.K.), Eugene Feiner Laboratory for Vascular Biology and Thrombosis (A.D.E.), Laboratory for Cardiac Stem Cell and Gene Therapy (G.Q., K.P., P.M.), Center for Translational Medicine, Thomas Jefferson University, 19107 Philadelphia, PA, USA.
Henriette BrinksCenter for Molecular and Translational Cardiology (M.V, C.W., N.H., K.S., P.M.), Department of Internal Medicine III (O.J.M, S.S., H.J.H., H.A.K.), Division of Cardiology, INF 350, University of Heidelberg, 69120 Heidelberg, Germany; Institute of Physiology and Pathophysiology (F.W., O.F.) Medical Biophysics, INF 326, University of Heidelberg, 69120 Heidelberg, Germany; George Zallie & Family Laboratory for Cardiovascular Gene Therapy (J.E.R., H.B., W.J.K.), Eugene Feiner Laboratory for Vascular Biology and Thrombosis (A.D.E.), Laboratory for Cardiac Stem Cell and Gene Therapy (G.Q., K.P., P.M.), Center for Translational Medicine, Thomas Jefferson University, 19107 Philadelphia, PA, USA.
Hugo A KatusCenter for Molecular and Translational Cardiology (M.V, C.W., N.H., K.S., P.M.), Department of Internal Medicine III (O.J.M, S.S., H.J.H., H.A.K.), Division of Cardiology, INF 350, University of Heidelberg, 69120 Heidelberg, Germany; Institute of Physiology and Pathophysiology (F.W., O.F.) Medical Biophysics, INF 326, University of Heidelberg, 69120 Heidelberg, Germany; George Zallie & Family Laboratory for Cardiovascular Gene Therapy (J.E.R., H.B., W.J.K.), Eugene Feiner Laboratory for Vascular Biology and Thrombosis (A.D.E.), Laboratory for Cardiac Stem Cell and Gene Therapy (G.Q., K.P., P.M.), Center for Translational Medicine, Thomas Jefferson University, 19107 Philadelphia, PA, USA.
Walter J KochCenter for Molecular and Translational Cardiology (M.V, C.W., N.H., K.S., P.M.), Department of Internal Medicine III (O.J.M, S.S., H.J.H., H.A.K.), Division of Cardiology, INF 350, University of Heidelberg, 69120 Heidelberg, Germany; Institute of Physiology and Pathophysiology (F.W., O.F.) Medical Biophysics, INF 326, University of Heidelberg, 69120 Heidelberg, Germany; George Zallie & Family Laboratory for Cardiovascular Gene Therapy (J.E.R., H.B., W.J.K.), Eugene Feiner Laboratory for Vascular Biology and Thrombosis (A.D.E.), Laboratory for Cardiac Stem Cell and Gene Therapy (G.Q., K.P., P.M.), Center for Translational Medicine, Thomas Jefferson University, 19107 Philadelphia, PA, USA.
Andrea D EckhartCenter for Molecular and Translational Cardiology (M.V, C.W., N.H., K.S., P.M.), Department of Internal Medicine III (O.J.M, S.S., H.J.H., H.A.K.), Division of Cardiology, INF 350, University of Heidelberg, 69120 Heidelberg, Germany; Institute of Physiology and Pathophysiology (F.W., O.F.) Medical Biophysics, INF 326, University of Heidelberg, 69120 Heidelberg, Germany; George Zallie & Family Laboratory for Cardiovascular Gene Therapy (J.E.R., H.B., W.J.K.), Eugene Feiner Laboratory for Vascular Biology and Thrombosis (A.D.E.), Laboratory for Cardiac Stem Cell and Gene Therapy (G.Q., K.P., P.M.), Center for Translational Medicine, Thomas Jefferson University, 19107 Philadelphia, PA, USA.
Oliver Friedrich *Center for Molecular and Translational Cardiology (M.V, C.W., N.H., K.S., P.M.), Department of Internal Medicine III (O.J.M, S.S., H.J.H., H.A.K.), Division of Cardiology, INF 350, University of Heidelberg, 69120 Heidelberg, Germany; Institute of Physiology and Pathophysiology (F.W., O.F.) Medical Biophysics, INF 326, University of Heidelberg, 69120 Heidelberg, Germany; George Zallie & Family Laboratory for Cardiovascular Gene Therapy (J.E.R., H.B., W.J.K.), Eugene Feiner Laboratory for Vascular Biology and Thrombosis (A.D.E.), Laboratory for Cardiac Stem Cell and Gene Therapy (G.Q., K.P., P.M.), Center for Translational Medicine, Thomas Jefferson University, 19107 Philadelphia, PA, USA.
Patrick Most *Center for Molecular and Translational Cardiology (M.V, C.W., N.H., K.S., P.M.), Department of Internal Medicine III (O.J.M, S.S., H.J.H., H.A.K.), Division of Cardiology, INF 350, University of Heidelberg, 69120 Heidelberg, Germany; Institute of Physiology and Pathophysiology (F.W., O.F.) Medical Biophysics, INF 326, University of Heidelberg, 69120 Heidelberg, Germany; George Zallie & Family Laboratory for Cardiovascular Gene Therapy (J.E.R., H.B., W.J.K.), Eugene Feiner Laboratory for Vascular Biology and Thrombosis (A.D.E.), Laboratory for Cardiac Stem Cell and Gene Therapy (G.Q., K.P., P.M.), Center for Translational Medicine, Thomas Jefferson University, 19107 Philadelphia, PA, USA.
Heidelberg University · DE

Funding

Regulation of Beta-Adrenergic Receptor Signaling by S-NitrosylationP01HL075443 · NHLBI · DUKE UNIVERSITY · PI STAMLER, JONATHAN S. · 2004 to 2019
$26.1M
Targeted Cancer Therapeutics and Heart Failure: Mechanisms and Post-injury RepairP01HL091799 · NHLBI · THOMAS JEFFERSON UNIVERSITY · PI HOUSER, STEVEN R · 2008 to 2018
$23.1M
Targeting GRK2 in the HeartR01HL061690 · NHLBI · THOMAS JEFFERSON UNIVERSITY · PI KOCH, WALTER J. · 1998 to 2022
$4.2M
Targeting GRK2 (BARK1) in Heart FailureR37HL061690 · NHLBI · THOMAS JEFFERSON UNIVERSITY · PI KOCH, WALTER J. · 2009 to 2018
$3.9M
Gene Transfer and Myocardial FunctionR01HL056205 · NHLBI · THOMAS JEFFERSON UNIVERSITY · PI KOCH, WALTER J. · 1998 to 2008
$2.6M
S100A1: A Novel Modulator of Myocardial Infarct Inflammation and RegenerationR01HL092130 · NHLBI · THOMAS JEFFERSON UNIVERSITY · PI PEPPEL, KARSTEN · 2008 to 2012
$2.2M
NHLBI NIH HHS P01 HL075443NHLBI NIH HHS P01 HL091799NHLBI NIH HHS R01 HL056205NHLBI NIH HHS R01 HL061690NHLBI NIH HHS R01 HL092130NHLBI NIH HHS R01 HL56205NHLBI NIH HHS R01 HL92130NHLBI NIH HHS R01 HL92130-02S1NHLBI NIH HHS R37 HL061690
6 · The paper itself

Abstract

rationaleThe G(βγ)-sequestering peptide β-adrenergic receptor kinase (βARK)ct derived from the G-protein-coupled receptor kinase (GRK)2 carboxyl terminus has emerged as a promising target for gene-based heart failure therapy. Enhanced downstream cAMP signaling has been proposed as the underlying mechanism for increased β-adrenergic receptor (βAR) responsiveness. However, molecular targets mediating improved cardiac contractile performance by βARKct and its impact on G(βγ)-mediated signaling have yet to be fully elucidated.

objectiveWe sought to identify G(βγ)-regulated targets and signaling mechanisms conveying βARKct-mediated enhanced βAR responsiveness in normal (NC) and failing (FC) adult rat ventricular cardiomyocytes. METHODS AND

resultsAssessing viral-based βARKct gene delivery with electrophysiological techniques, analysis of contractile performance, subcellular Ca²(+) handling, and site-specific protein phosphorylation, we demonstrate that βARKct enhances the cardiac L-type Ca²(+) channel (LCC) current (I(Ca)) both in NCs and FCs on βAR stimulation. Mechanistically, βARKct augments I(Ca) by preventing enhanced inhibitory interaction between the α1-LCC subunit (Cav1.2α) and liberated G(βγ) subunits downstream of activated βARs. Despite improved βAR contractile responsiveness, βARKct neither increased nor restored cAMP-dependent protein kinase (PKA) and calmodulin-dependent kinase II signaling including unchanged protein kinase (PK)Cε, extracellular signal-regulated kinase (ERK)1/2, Akt, ERK5, and p38 activation both in NCs and FCs. Accordingly, although βARKct significantly increases I(Ca) and Ca²(+) transients, being susceptible to suppression by recombinant G(βγ) protein and use-dependent LCC blocker, βARKct-expressing cardiomyocytes exhibit equal basal and βAR-stimulated sarcoplasmic reticulum Ca²(+) load, spontaneous diastolic Ca²(+) leakage, and survival rates and were less susceptible to field-stimulated Ca²(+) waves compared with controls.

conclusionOur study identifies a G(βγ)-dependent signaling pathway attenuating cardiomyocyte I(Ca) on βAR as molecular target for the G(βγ)-sequestering peptide βARKct. Targeted interruption of this inhibitory signaling pathway by βARKct confers improved βAR contractile responsiveness through increased I(Ca) without enhancing regular or restoring abnormal cAMP-signaling. βARKct-mediated improvement of I(Ca) rendered cardiomyocytes neither susceptible to βAR-induced damage nor arrhythmogenic sarcoplasmic reticulum Ca²(+) leakage.

Indexed as

G-Protein-Coupled Receptor Kinase 2Heart FailureAnimalsCalciumCalcium Channels, L-TypeCardiotonic AgentsCell SurvivalGenetic TherapyGTP-Binding Protein beta SubunitsGTP-Binding Protein gamma SubunitsHeart VentriclesMAP Kinase Signaling SystemMyocardial ContractionMyocytes, CardiacPeptidesProtein KinasesCacna1c protein, ratCalciumCalcium Channels, L-TypeCardiotonic AgentsG-Protein-Coupled Receptor Kinase 2Grk2 protein, ratGTP-Binding Protein beta SubunitsGTP-Binding Protein gamma SubunitsPeptidesProtein Kinases

Identifiers

PMID21106943
PMCPMC4013502
OpenAlexW2021006625

What OpenQuestion holds

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Read underepoch 390

Registered trials

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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.