Na ⁺/Ca ²⁺ exchanger-1 protects against systolic failure in the Akita ^ins2 model of diabetic cardiomyopathy via a CXCR4/NF-κB pathway

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.