Document Detail


Cardiac resynchronization sensitizes the sarcomere to calcium by reactivating GSK-3β.
MedLine Citation:
PMID:  24292707     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Cardiac resynchronization therapy (CRT), the application of biventricular stimulation to correct discoordinate contraction, is the only heart failure treatment that enhances acute and chronic systolic function, increases cardiac work, and reduces mortality. Resting myocyte function also increases after CRT despite only modest improvement in calcium transients, suggesting that CRT may enhance myofilament calcium responsiveness. To test this hypothesis, we examined adult dogs subjected to tachypacing-induced heart failure for 6 weeks, concurrent with ventricular dyssynchrony (HF(dys)) or CRT. Myofilament force-calcium relationships were measured in skinned trabeculae and/or myocytes. Compared with control, maximal calcium-activated force and calcium sensitivity declined globally in HF(dys); however, CRT restored both. Phosphatase PP1 induced calcium desensitization in control and CRT-treated cells, while HF(dys) cells were unaffected, implying that CRT enhances myofilament phosphorylation. Proteomics revealed phosphorylation sites on Z-disk and M-band proteins, which were predicted to be targets of glycogen synthase kinase-3β (GSK-3β). We found that GSK-3β was deactivated in HF(dys) and reactivated by CRT. Mass spectrometry of myofilament proteins from HF(dys) animals incubated with GSK-3β confirmed GSK-3β–dependent phosphorylation at many of the same sites observed with CRT. GSK-3β restored calcium sensitivity in HF(dys), but did not affect control or CRT cells. These data indicate that CRT improves calcium responsiveness of myofilaments following HF(dys) through GSK-3β reactivation, identifying a therapeutic approach to enhancing contractile function
Authors:
Jonathan A Kirk; Ronald J Holewinski; Viola Kooij; Giulio Agnetti; Richard S Tunin; Namthip Witayavanitkul; Pieter P de Tombe; Wei Dong Gao; Jennifer Van Eyk; David A Kass
Related Documents :
23890117 - Emerging roles for native orai ca(2+) channels in cardiovascular disease.
3663137 - Binding of inositol phosphates and induction of ca2+ release from pituitary microsomal ...
2673237 - Effects of heparin on inositol 1,4,5-trisphosphate and guanosine 5'-o-(3-thio triphosph...
1362247 - Occurrence and functions of the phosphatidylinositol cycle in the myocardium.
9174647 - Differences in ca2+ pumping activity between sub-populations of human red cells.
8437107 - Two delayed rectifiers in guinea pig ventricular myocytes distinguished by tail current...
Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  124     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2014 Jan 
Date Detail:
Created Date:  2014-02-12     Completed Date:  2014-03-03     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  129-38     Citation Subset:  AIM; IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Calcium / metabolism*
Cardiac Resynchronization Therapy
Cell Enlargement
Dogs
Enzyme Activation
Glycogen Synthase Kinase 3 / metabolism*
Heart Failure / enzymology*,  therapy
Heart Ventricles / pathology
Myocardial Contraction
Myofibrils / physiology
Phosphorylation
Protein Processing, Post-Translational*
Sarcomeres / metabolism*
Troponin I / metabolism
Troponin T / metabolism
Grant Support
ID/Acronym/Agency:
HHSN268201000032C//PHS HHS; HL62426/HL/NHLBI NIH HHS; HV-10-05/HV/NHLBI NIH HHS; P01 HL062426/HL/NHLBI NIH HHS; P01-HL077180/HL/NHLBI NIH HHS; R01 HL075494/HL/NHLBI NIH HHS; T32 HL007227/HL/NHLBI NIH HHS; T32-HL007227/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Troponin I; 0/Troponin T; EC 2.7.11.26/Glycogen Synthase Kinase 3; SY7Q814VUP/Calcium
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients.
Next Document:  Aptamer-targeted inhibition of mTOR in T cells enhances antitumor immunity.