Evidence map›Paper›PMID 26477830›Full record

ArticleCirculation. Heart failure2015

Molecular Screen Identifies Cardiac Myosin-Binding Protein-C as a Protein Kinase G-Iα Substrate.

Robrecht Thoonen, Shewit Giovanni, Suresh Govindan, Dong I Lee, Guang-Rong Wang, Timothy D Calamaras, Eiki Takimoto, David A Kass, Sakthivel Sadayappan, Robert M Blanton

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

Article in Circulation. Heart failure, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.

0numbers the graph read from it
0cells of the map it votes in
28citing papers in PubMed
1.7field-weighted citation impact, top 14% 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

28 citing papers in PubMed, 43 citations in OpenAlex.

  1. Observational
  2. Review
  3. Article
  4. Article
  5. Review
  6. Review
  7. Article
  8. Article
  9. Review
  10. New Therapeutics for Heart Failure: Focusing on cGMP Signaling.International journal of molecular sciences · 2023
    Review
  11. Review
  12. Article
  13. Cyclic GMP and PKG Signaling in Heart Failure.Frontiers in pharmacology · 2022
    Review
  14. Article
  15. Article
  16. Article
  17. Article
  18. Article
  19. Review
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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

10 authors at 3 institutions in 1 country.

Robrecht ThoonenFrom the Molecular Cardiology Research Institute (R.T., G.-R.W., T.D.C., R.M.B.) and Division of Cardiology (R.M.B.), Tufts Medical Center, Boston, MA; Tufts University School of Medicine, Boston, MA (S. Giovanni); Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S. Govindan, S.S.); Johns Hopkins Medical Institutions, Baltimore, MD (D.I.L., E.T., D.A.K.); and Department of Cardiovascular Medicine, The University of Tokyo, Tokyo, Japan (E.T.).
Shewit GiovanniFrom the Molecular Cardiology Research Institute (R.T., G.-R.W., T.D.C., R.M.B.) and Division of Cardiology (R.M.B.), Tufts Medical Center, Boston, MA; Tufts University School of Medicine, Boston, MA (S. Giovanni); Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S. Govindan, S.S.); Johns Hopkins Medical Institutions, Baltimore, MD (D.I.L., E.T., D.A.K.); and Department of Cardiovascular Medicine, The University of Tokyo, Tokyo, Japan (E.T.).
Suresh GovindanFrom the Molecular Cardiology Research Institute (R.T., G.-R.W., T.D.C., R.M.B.) and Division of Cardiology (R.M.B.), Tufts Medical Center, Boston, MA; Tufts University School of Medicine, Boston, MA (S. Giovanni); Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S. Govindan, S.S.); Johns Hopkins Medical Institutions, Baltimore, MD (D.I.L., E.T., D.A.K.); and Department of Cardiovascular Medicine, The University of Tokyo, Tokyo, Japan (E.T.).
Dong I LeeFrom the Molecular Cardiology Research Institute (R.T., G.-R.W., T.D.C., R.M.B.) and Division of Cardiology (R.M.B.), Tufts Medical Center, Boston, MA; Tufts University School of Medicine, Boston, MA (S. Giovanni); Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S. Govindan, S.S.); Johns Hopkins Medical Institutions, Baltimore, MD (D.I.L., E.T., D.A.K.); and Department of Cardiovascular Medicine, The University of Tokyo, Tokyo, Japan (E.T.).
Guang-Rong WangFrom the Molecular Cardiology Research Institute (R.T., G.-R.W., T.D.C., R.M.B.) and Division of Cardiology (R.M.B.), Tufts Medical Center, Boston, MA; Tufts University School of Medicine, Boston, MA (S. Giovanni); Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S. Govindan, S.S.); Johns Hopkins Medical Institutions, Baltimore, MD (D.I.L., E.T., D.A.K.); and Department of Cardiovascular Medicine, The University of Tokyo, Tokyo, Japan (E.T.).
Timothy D CalamarasFrom the Molecular Cardiology Research Institute (R.T., G.-R.W., T.D.C., R.M.B.) and Division of Cardiology (R.M.B.), Tufts Medical Center, Boston, MA; Tufts University School of Medicine, Boston, MA (S. Giovanni); Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S. Govindan, S.S.); Johns Hopkins Medical Institutions, Baltimore, MD (D.I.L., E.T., D.A.K.); and Department of Cardiovascular Medicine, The University of Tokyo, Tokyo, Japan (E.T.).
Eiki TakimotoFrom the Molecular Cardiology Research Institute (R.T., G.-R.W., T.D.C., R.M.B.) and Division of Cardiology (R.M.B.), Tufts Medical Center, Boston, MA; Tufts University School of Medicine, Boston, MA (S. Giovanni); Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S. Govindan, S.S.); Johns Hopkins Medical Institutions, Baltimore, MD (D.I.L., E.T., D.A.K.); and Department of Cardiovascular Medicine, The University of Tokyo, Tokyo, Japan (E.T.).
David A KassFrom the Molecular Cardiology Research Institute (R.T., G.-R.W., T.D.C., R.M.B.) and Division of Cardiology (R.M.B.), Tufts Medical Center, Boston, MA; Tufts University School of Medicine, Boston, MA (S. Giovanni); Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S. Govindan, S.S.); Johns Hopkins Medical Institutions, Baltimore, MD (D.I.L., E.T., D.A.K.); and Department of Cardiovascular Medicine, The University of Tokyo, Tokyo, Japan (E.T.).
Sakthivel SadayappanFrom the Molecular Cardiology Research Institute (R.T., G.-R.W., T.D.C., R.M.B.) and Division of Cardiology (R.M.B.), Tufts Medical Center, Boston, MA; Tufts University School of Medicine, Boston, MA (S. Giovanni); Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S. Govindan, S.S.); Johns Hopkins Medical Institutions, Baltimore, MD (D.I.L., E.T., D.A.K.); and Department of Cardiovascular Medicine, The University of Tokyo, Tokyo, Japan (E.T.).
Robert M BlantonFrom the Molecular Cardiology Research Institute (R.T., G.-R.W., T.D.C., R.M.B.) and Division of Cardiology (R.M.B.), Tufts Medical Center, Boston, MA; Tufts University School of Medicine, Boston, MA (S. Giovanni); Department of Cell and Molecular Physiology, Health Sciences Division, Loyola University Chicago, Maywood, IL (S. Govindan, S.S.); Johns Hopkins Medical Institutions, Baltimore, MD (D.I.L., E.T., D.A.K.); and Department of Cardiovascular Medicine, The University of Tokyo, Tokyo, Japan (E.T.). rblanton@tuftsmedicalcenter.org.
Loyola University Chicago · USJohns Hopkins University · USTufts University · US

Funding

Fast myosin binding protein-C and cardiac contractility in heart failureR01HL105826 · NHLBI · UNIVERSITY OF CINCINNATI · PI SADAYAPPAN, SAKTHIVEL · 2011 to 2025
$4.5M
Tufts Clinical and Translational Research InstituteKL2TR001063 · NCATS · TUFTS UNIVERSITY BOSTON · PI SELKER, HARRY P. · 2013 to 2017
$2.1M
Proteomic approaches to validate novel cardiac biomarkers for myocardial infarctiK02HL114749 · NHLBI · UNIVERSITY OF CINCINNATI · PI SADAYAPPAN, SAKTHIVEL · 2012 to 2016
$498k
Cardiac Myocyte-Specific Role of PKG I Alpha in Aging-Dependent Cardiac RemodelinR03AG042367 · NIA · TUFTS MEDICAL CENTER · PI BLANTON, ROBERT MORRIS · 2012 to 2013
$155k
NCATS NIH HHS 1KL2TR001063-01NCATS NIH HHS KL2 TR001063NHLBI NIH HHS K02 HL114749NHLBI NIH HHS K02HL114749NHLBI NIH HHS L30 HL105132NHLBI NIH HHS R01 HL105826NHLBI NIH HHS R01HL105826NIA NIH HHS 1R03AG042367NIA NIH HHS R03 AG042367
6 · The paper itself

Abstract

backgroundPharmacological activation of cGMP-dependent protein kinase G I (PKGI) has emerged as a therapeutic strategy for humans with heart failure. However, PKG-activating drugs have been limited by hypotension arising from PKG-induced vasodilation. PKGIα antiremodeling substrates specific to the myocardium might provide targets to circumvent this limitation, but currently remain poorly understood. METHODS AND

resultsWe performed a screen for myocardial proteins interacting with the PKGIα leucine zipper (LZ)-binding domain to identify myocardial-specific PKGI antiremodeling substrates. Our screen identified cardiac myosin-binding protein-C (cMyBP-C), a cardiac myocyte-specific protein, which has been demonstrated to inhibit cardiac remodeling in the phosphorylated state, and when mutated leads to hypertrophic cardiomyopathy in humans. GST pulldowns and precipitations with cGMP-conjugated beads confirmed the PKGIα-cMyBP-C interaction in myocardial lysates. In vitro studies demonstrated that purified PKGIα phosphorylates the cMyBP-C M-domain at Ser-273, Ser-282, and Ser-302. cGMP induced cMyBP-C phosphorylation at these residues in COS cells transfected with PKGIα, but not in cells transfected with LZ mutant PKGIα, containing mutations to disrupt LZ substrate binding. In mice subjected to left ventricular pressure overload, PKGI activation with sildenafil increased cMyBP-C phosphorylation at Ser-273 compared with untreated mice. cGMP also induced cMyBP-C phosphorylation in isolated cardiac myocytes.

conclusionsTaken together, these data support that PKGIα and cMyBP-C interact in the heart and that cMyBP-C is an anti remodeling PKGIα kinase substrate. This study provides the first identification of a myocardial-specific PKGIα LZ-dependent antiremodeling substrate and supports further exploration of PKGIα myocardial LZ substrates as potential therapeutic targets for heart failure.

Indexed as

AnimalsCarrier ProteinsCyclic GMPCyclic GMP-Dependent Protein Kinase Type IDisease Models, AnimalHeart FailureMiceMice, Inbred C57BLMyocytes, CardiacMyosin Binding Protein CPhosphorylationRatsRats, Sprague-DawleyCarrier ProteinsCyclic GMPCyclic GMP-Dependent Protein Kinase Type IMyosin Binding Protein Ccyclic GMP-dependent protein kinase type Iheart failureleucine zippersmyosin-binding protein Cventricular remodeling

Identifiers

PMID26477830
PMCPMC4651836
OpenAlexW2173380255

What OpenQuestion holds

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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.