Abstract 3803: Myocardial CXCR4 Gene Transfer Negatively Modulates Cardiac Function Following Ischemia-Reperfusion Injury
The chemokine, stromal cell-derived factor-1alpha (SDF-1α, CXCL12), and its receptor, CXCR4, are key mediators of stem cell homing and retention. Their role in modulating cardiac function following myocardial ischemic/reperfusion injury (IRI) is less well defined. Previous data from our group has shown that SDF activation of endogenous CXCR4 expressed on cardiac myocytes negatively modulated contractility and calcium flux in vitro. The objective of the present study was to examine the effects of over expression of CXCR4 in the heart, using cardiac gene transfer, following I/R in vivo. Adult rats underwent direct cardiac gene transfer using adenoviral vectors with constructs expressing either CXCR4 (ad.CXCR4), beta-galactosidase (ad.β-gal) or normal saline (NS) using standard cross-clamping technique. Seven days post adenoviral infection, animals underwent IRI and then were sacrificed 24 h post surgery. The efficiency of gene transfer was verified by staining with either X-gal or with an anti-CXCR4 antibody as well as immunoblotting. Infarct size and cardiac function were determined by TTC staining and by echocardiography, respectively. The infarct to left ventricle area ratio was increased in the ad.CXCR4 infected hearts (13.5% ± 4.1%, n = 9) compared to the ad. β-gal infected hearts (7.6% ± 3.4%, n = 11) and NS injected hearts (8.0% ± 2.0%, n = 6). Fractional shortening (FS) was decreased in the ad.CXCR4 (38% ± 5%) as compared to ad. β-gal (46% ± 6%) and NS (48% ± 7%) animals. Sham operated rats had a FS of 61% ± 5%, n=11. Histological analyses of sections from the ad.CXCR4 infected hearts, demonstrated an increase in leukocyte infiltration as determined by CD45 staining compared to ad.β-gal and NS hearts. There was no significant difference, between the groups, in numbers of infiltrating macrophages. In conclusion, overexpression of myocardial CXCR4 resulted in larger infarcts and worsening contractile function following IRI. Strategies that enhance SDF1/CXCR4 expression and/or signaling in the heart to promote stem cells mobilization and engraftment may need to factor for the direct potentially negative inotropic effects of CXCR4 activation.