Abstract 15646: Role of SDF-1/CXCR4 Axis in Diabetic Cardiomyopathy
Introduction: Diabetes is associated with a defect in stem cell homing due to blunted SDF-1 signaling. We investigated the role of the SDF-1:CXCR4 axis in diabetic cardiomyopathy (DCM).
Hypothesis: In this study we define a novel role for the SDF-1:CXCR4 axis in the hibernation and treatment of myocardial tissue in DCM.
Methods: Wild-type and cardiac CXCR4 null (CM-CXCR4 null) mice were randomly assigned to low fat diet (LFD, 10 kcal% fat) or High fat diet (HFD, 60% kcal% fat) for 5-8 months. Serial echocardiography was used to assess cardiac function. hSDF-1 plasmid (80 ug) was injected into the LV wall of half group of the 27-week-old HFD mice. SDF-1, CXCR4, SIRT1, SIRT3, and SIRT6 mRNA levels in the hearts were quantified by qPCR at different times. Myocardial blood flow (MBF) was measurement by contrast echocardiography at baseline and during NE injection (5 ug/kg/min for 3 minutes).
Results: Compared to age-matched LFD mice, we observed a significant decrease in vascular density and a significant increase (66%) in cardiac CXCR4 expression prior to evidence of DCM. 25-week-old HFD mice showed 40% decrease in Ejection Fraction (EF). Direct myocardial injection of hSDF-1 plasmid led to a 34% and 45% improvement in EF 1 and 3 week later, respectively, compared to control. To determine if CM CXCR4 expression induces CM hibernation as a mechanism of DCM we quantified cardiac function in HFD CM-CXCR4 null mice. We observed an early loss of cardiac function in HFD CM-CXCR4 null mice compare to HFD control mice. Interestingly SIRT1 and SIRT6 were statistically decreased in HFD mice, suggesting that SIRT signaling may be involved in blunted SDF-1 signaling in DCM. SIRT expression was normalized in response to SDF-1 over-expression in DCM. Compared to LFD mice, HFD mice showed 28% decreased MBF reserve; SDF-1 plasmid treatment led to 35% increase of MBF reserve compared to control HFD mice.
Conclusions: Our data demonstrate that the SDF-1:CXCR4 axis has an important role in DCM. Our data suggests that cardiac myocyte over-expression of CXCR4 is involved in cardiac myocyte hibernation and can be reversed through SDF-1 over-expression. These data suggest that modulation of SDF-1/CXCR4 expression will delay or alleviate DCM.
Author Disclosures: M. Mayorga: None. M. Kiedrowski: None. M. Penn: None. F. Dong: None.
- © 2016 by American Heart Association, Inc.