Document Detail


Calcium cycling proteins and heart failure: mechanisms and therapeutics.
MedLine Citation:
PMID:  23281409     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Ca2+-dependent signaling is highly regulated in cardiomyocytes and determines the force of cardiac muscle contraction. Ca2+ cycling refers to the release and reuptake of intracellular Ca2+ that drives muscle contraction and relaxation. In failing hearts, Ca2+ cycling is profoundly altered, resulting in impaired contractility and fatal cardiac arrhythmias. The key defects in Ca2+ cycling occur at the level of the sarcoplasmic reticulum (SR), a Ca2+ storage organelle in muscle. Defects in the regulation of Ca2+ cycling proteins including the ryanodine receptor 2, cardiac (RyR2)/Ca2+ release channel macromolecular complexes and the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a (SERCA2a)/phospholamban complex contribute to heart failure. RyR2s are oxidized, nitrosylated, and PKA hyperphosphorylated, resulting in "leaky" channels in failing hearts. These leaky RyR2s contribute to depletion of Ca2+ from the SR, and the leaking Ca2+ depolarizes cardiomyocytes and triggers fatal arrhythmias. SERCA2a is downregulated and phospholamban is hypophosphorylated in failing hearts, resulting in impaired SR Ca2+ reuptake that conspires with leaky RyR2 to deplete SR Ca2+. Two new therapeutic strategies for heart failure (HF) are now being tested in clinical trials: (a) fixing the leak in RyR2 channels with a novel class of Ca2+-release channel stabilizers called Rycals and (b) increasing expression of SERCA2a to improve SR Ca2+ reuptake with viral-mediated gene therapy. There are many potential opportunities for additional mechanism-based therapeutics involving the machinery that regulates Ca2+ cycling in the heart.
Authors:
Andrew R Marks
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Review     Date:  2013-01-02
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-01-02     Completed Date:  2013-03-11     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  46-52     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Arrhythmias, Cardiac / etiology,  metabolism,  pathology,  physiopathology
Calcium / metabolism*
Calcium Channels / metabolism*
Calcium-Binding Proteins / metabolism*
Clinical Trials as Topic
Heart Failure / complications,  drug therapy,  metabolism*,  pathology,  physiopathology
Humans
Muscle Proteins / metabolism*
Myocardial Contraction
Myocardium / metabolism*,  pathology
Phosphorylation
Sarcoplasmic Reticulum / metabolism,  pathology
Grant Support
ID/Acronym/Agency:
R01 HL061503/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Calcium Channels; 0/Calcium-Binding Proteins; 0/Muscle Proteins; SY7Q814VUP/Calcium
Comments/Corrections

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