Abstract 3330: Genetic Deletion of CXCR4 in Cardiomyocytes Leads to Heart Failure
Objective: The CXC chemokine receptor 4 (CXCR4) is essential for hematopoiesis and vasculogenesis and is currently being validated as a therapeutic target for the recruitment of bone marrow progenitor cells for vascular repair. Its function in cardiomyocytes, however, is unknown.
Methods and Results: We first analyzed CXCR4 expression in mouse hearts. Both immunostaining for CXCR4 and the GFP expression from CXCR4BAC-GFP transgenic mice revealed a uniformed CXCR4 expression in cardiomyocytes at steady state. We then generated MHC-Cre/CXCR4floxed/floxed mice, in which the CXCR4 gene was deleted specifically in cardiomyocytes. The F1 generation of the MHC-Cre/CXCR4floxed/floxed (KO) mice and MHC-Cre/CXCR+/+ (WT) littermates from the MHC-Cre/CXCR4floxed/+ parents were used for the experiments. The heart function was evaluated at 2 months of age with Echocardiography. The KO mice exhibit an enlarged left ventricle accompanied by a significant reduction in ejection fraction (KO vs. WT: 36.2±5.68% vs. 66.7±7.62%, n=5, p=0.01) and fraction shortening (KO vs. WT: 17.1±2.94% vs. 37.1±6.31%, p=0.02) as compared to WT mice. The heart rate was significantly higher in KO mice than in WT mice (KO vs. WT: 524±120 vs. 403±90 beat per minute, under anesthesia, p=0.03). The worsened cardiac function in KO mice was associated with a greater heart/body weight ratio (mg/g) (KO vs. WT: 5.4±0.3 vs. 4.3±0.1, p=0.016). Histological analyses with Sirius red/fast green and Masson Trichrome staining revealed dramatic interstitial fibrosis in the hearts of KO but not WT mice. Since CXCR4 is a G protein-coupled receptor and G protein has been shown to regulate cardiac contractile function through cAMP/PKA pathway, we measured cAMP levels (ELISA) in the lysates prepared from KO and WT mouse cardiac tissues. Interestingly, we found a significantly lower level of cAMP in the KO hearts than in the WT hearts. These results suggest that CXCR4 may regulate cardiac function via cAMP/PKA signaling pathway.
Conclusion: CXCR4 expression in cardiomyocytes is essential for the maintenance of normal heart function.
This research has received full or partial funding support from the American Heart Association, National Center.