NDLI: Na+/Ca2+ exchanger-1 protects against systolic failure in the Akitains2 model of diabetic cardiomyopathy via a CXCR4/NF-κB pathway

Content Provider	PubMed Central
Author	Larocca, Thomas J. Fabris, Frank Chen, Jiqiu Daniel, Benhayon Zhang, Shihong Mccollum, Latronya Schecter, Alison D. Cheung, Joseph Y. Sobie, Eric A. Hajjar, Roger J. Lebeche, Djamel
Copyright Year	2012
Abstract	Diabetic cardiomyopathy is characterized, in part, by calcium handling imbalances associated with ventricular dysfunction. The cardiac Na+/Ca2+ 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 Akitains2 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 Akitains2 mouse was monitored using echocardiography and in vivo pressure-volume analysis. The Akitains2 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 Ca2+-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 Akitains2 mouse. CXCL12 and CXCR4 were both upregulated in the Akitains2 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 Akitains2 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.
Related Links	http://dx.doi.org/10.1152/ajpheart.01198.2011
Starting Page	353
File Format	PDF
ISSN	03636135
e-ISSN	15221539
Journal	American Journal of Physiology - Heart and Circulatory Physiology
Issue Number	3
Volume Number	303
Language	English
Publisher	American Physiological Society
Publisher Date	2012-08-01
Access Restriction	Open
Rights Holder	American Physiological Society
Subject Keyword	Physiology (medical) Physiology Cardiology and Cardiovascular Medicine Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Physiology Physiology (medical) Cardiology and Cardiovascular Medicine

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