Document Detail


Na+/Ca2+ exchanger-1 protects against systolic failure in the Akitains2 model of diabetic cardiomyopathy via a CXCR4/NF-κB pathway.
MedLine Citation:
PMID:  22610174     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Diabetic cardiomyopathy is characterized, in part, by calcium handling imbalances associated with ventricular dysfunction. The cardiac Na(+)/Ca(2+) exchanger 1 (NCX1) has been implicated as a compensatory mechanism in response to reduced contractility in the heart; however, its role in diabetic cardiomyopathy remains unknown. We aimed to fully characterize the Akita(ins2) murine model of type 1 diabetes through assessing cardiac function and NCX1 regulation. The CXCL12/CXCR4 chemokine axis is well described in its cardioprotective effects via progenitor cell recruitment postacute myocardial infarction; however, it also functions in regulating calcium dependent processes in the cardiac myocyte. We therefore investigated the potential impact of CXCR4 in diabetic cardiomyopathy. Cardiac performance in the Akita(ins2) mouse was monitored using echocardiography and in vivo pressure-volume analysis. The Akita(ins2) mouse is protected against ventricular systolic failure evident at both 5 and 12 mo of age. However, the preserved contractility was associated with a decreased sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a)/phospholamban ratio and increased NCX1 content. Direct myocardial injection of adenovirus encoding anti-sense NCX1 significantly decreased NCX1 expression and induced systolic failure in the Akita(ins2) mouse. CXCL12 and CXCR4 were both upregulated in the Akita(ins2) heart, along with an increase in IκB-α and NF-κB p65 phosphorylation. We demonstrated that CXCR4 activation upregulates NCX1 expression through a NF-κB-dependent signaling pathway in the cardiac myocyte. In conclusion, the Akita(ins2) type 1 diabetic model is protected against systolic failure due to increased NCX1 expression. In addition, our studies reveal a novel role of CXCR4 in the diabetic heart by regulating NCX1 expression via a NF-κB-dependent mechanism.
Authors:
Thomas J LaRocca; Frank Fabris; Jiqiu Chen; Daniel Benhayon; Shihong Zhang; LaTronya McCollum; Alison D Schecter; Joseph Y Cheung; Eric A Sobie; Roger J Hajjar; Djamel Lebeche
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-05-18
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  303     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2012 Aug 
Date Detail:
Created Date:  2012-08-02     Completed Date:  2012-10-10     Revised Date:  2014-04-02    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H353-67     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Action Potentials
Animals
Calcium / metabolism
Cells, Cultured
Chemokine CXCL12 / metabolism
Diabetes Mellitus, Type 1 / complications*,  genetics,  metabolism
Diabetic Cardiomyopathies / etiology*,  genetics,  metabolism,  physiopathology,  prevention & control,  ultrasonography
Diastole
Disease Models, Animal
Gene Knockdown Techniques
Hemodynamics
Insulin / genetics
Male
Mice
Myocytes, Cardiac / metabolism*
NF-kappa B / metabolism*
Phosphorylation
Rats
Rats, Sprague-Dawley
Receptors, CXCR4 / metabolism*
Signal Transduction
Sodium-Calcium Exchanger / genetics,  metabolism*
Systole
Up-Regulation
Ventricular Dysfunction, Left / etiology,  genetics,  metabolism,  physiopathology,  prevention & control*,  ultrasonography
Ventricular Function, Left
Grant Support
ID/Acronym/Agency:
1F30HL096344/HL/NHLBI NIH HHS; T32 HL007824/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/CXCR4 protein, mouse; 0/Chemokine CXCL12; 0/Cxcl12 protein, mouse; 0/Cxcr4 protein, rat; 0/Ins2 protein, mouse; 0/Insulin; 0/NF-kappa B; 0/Receptors, CXCR4; 0/Sodium-Calcium Exchanger; 0/sodium-calcium exchanger 1; SY7Q814VUP/Calcium
Comments/Corrections

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


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