Document Detail


Loss of the AE3 anion exchanger in a hypertrophic cardiomyopathy model causes rapid decompensation and heart failure.
MedLine Citation:
PMID:  21056571     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The AE3 Cl(-)/HCO(3)(-) exchanger is abundantly expressed in the sarcolemma of cardiomyocytes, where it mediates Cl(-)-uptake and HCO(3)(-)-extrusion. Inhibition of AE3-mediated Cl(-)/HCO(3)(-) exchange has been suggested to protect against cardiac hypertrophy; however, other studies indicate that AE3 might be necessary for optimal cardiac function. To test these hypotheses we crossed AE3-null mice, which appear phenotypically normal, with a hypertrophic cardiomyopathy mouse model carrying a Glu180Gly mutation in α-tropomyosin (TM180). Loss of AE3 had no effect on hypertrophy; however, survival of TM180/AE3 double mutants was sharply reduced compared with TM180 single mutants. Analysis of cardiac performance revealed impaired cardiac function in TM180 and TM180/AE3 mutants. TM180/AE3 double mutants were more severely affected and exhibited little response to β-adrenergic stimulation, a likely consequence of their more rapid progression to heart failure. Increased expression of calmodulin-dependent kinase II and protein phosphatase 1 and differences in methylation and localization of protein phosphatase 2A were observed, but were similar in single and double mutants. Phosphorylation of phospholamban on Ser16 was sharply increased in both single and double mutants relative to wild-type hearts under basal conditions, leading to reduced reserve capacity for β-adrenergic stimulation of phospholamban phosphorylation. Imaging analysis of isolated myocytes revealed reductions in amplitude and decay of Ca(2+) transients in both mutants, with greater reductions in TM180/AE3 mutants, consistent with the greater severity of their heart failure phenotype. Thus, in the TM180 cardiomyopathy model, loss of AE3 had no apparent anti-hypertrophic effect and led to more rapid decompensation and heart failure.
Authors:
Nabeel J Al Moamen; Vikram Prasad; Ilona Bodi; Marian L Miller; Michelle L Neiman; Valerie M Lasko; Seth L Alper; David F Wieczorek; John N Lorenz; Gary E Shull
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2010-11-04
Journal Detail:
Title:  Journal of molecular and cellular cardiology     Volume:  50     ISSN:  1095-8584     ISO Abbreviation:  J. Mol. Cell. Cardiol.     Publication Date:  2011 Jan 
Date Detail:
Created Date:  2011-01-10     Completed Date:  2011-05-10     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  0262322     Medline TA:  J Mol Cell Cardiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  137-46     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier Ltd. All rights reserved.
Affiliation:
Department of Molecular Genetics, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Antiporters / metabolism*
Calcium / metabolism
Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
Cardiomyopathy, Hypertrophic / genetics,  metabolism*
Cation Transport Proteins
Female
Heart Failure / genetics,  metabolism*
Immunoblotting
Male
Mice
Mice, Mutant Strains
Mice, Transgenic
Myocytes, Cardiac / metabolism*,  pathology
Phosphoprotein Phosphatases / metabolism
Phosphorylation
Sodium-Hydrogen Antiporter
Grant Support
ID/Acronym/Agency:
DK043495/DK/NIDDK NIH HHS; HL061974/HL/NHLBI NIH HHS; HL081680/HL/NHLBI NIH HHS; R01 HL061974-11/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Antiporters; 0/Cation Transport Proteins; 0/Slc4a3 protein, mouse; 0/Slc9a1 protein, mouse; 0/Sodium-Hydrogen Antiporter; 7440-70-2/Calcium; EC 2.7.11.17/Calcium-Calmodulin-Dependent Protein Kinase Type 2; EC 3.1.3.16/Phosphoprotein Phosphatases
Comments/Corrections

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