Stromal Cell-Derived Factor 1 (SDF-1) and its Receptor CXCR4 Improve Diabetic Cardiomyopathy (DCM)

Abstract

In this study we define a novel role for the SDF-1/CXCR4 axis in the hibernation and treatment of myocardial tissue in diabetic cardiomyopathy (DCM). Wild-type and cardiac CXCR4 null (CM-CXCR4 null) mice were randomly assigned to low-fat diet (LFD) or high-fat diet (HFD) for 30 weeks. Serial echocardiography was used to assess cardiac function. SDF-1 plasmid (80 ug) was injected into the LV wall of half group of the HFD mice (27 weeks). SDF-1, CXCR4, SIRT1, SIRT3, and SIRT6 mRNA levels in the hearts were quantified by qPCR at different times. Compared to age-matched LFD mice, 27-week-old HFD mice showed a 33% decrease in Ejection Fraction (EF). Direct myocardial injection of hSDF-1 plasmid led to a 15% and 30% improvement in EF 1 and 3 weeks 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 compared 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. Our data demonstrated 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. These data suggest that modulation of SDF-1/CXCR4 expression will delay or alleviate DCM.