Abstract 3333: Chronic AMD3100 Antagonism of SDF1-CXCR4 Signaling Exacerbates Cardiac Injury After Myocardial Infarction Despite Increased Recruitment of ckitpos Progenitors
The SDF1-CXCR4 axis has been found to play an important role in survival signaling in the myocardium as well as promoting improved recovery after injury. To further define the role of SDF-CXCR4 in response to injury we used the CXCR4 antagonist AMD3100 (AMD) to block SDF1-CXCR4 interaction and activation after chronic coronary artery ligation. Mice were implanted with osmotic minipumps to begin chronic infusion of AMD (0.475 mg/kg/h) or PBS 24 h prior to coronary ligation. Cardiac function was determined by echocardiography 20 days after ligation, at which time hearts were analyzed for changes in morphometry. Biochemical analysis of hearts was performed 2 days after sham or ligation surgery with PBS or AMD infusion. Chronic administration of AMD significantly decreased cardiac function following myocardial infarction (MI). Echo analysis showed significant decreases in ejection fraction and fractional shortening in mice treated with AMD after MI which was accompanied by hypertrophy and increased systolic and diastolic LV chamber dimensions. Cardiac morphometric analysis showed the hearts of AMD treated mice after MI to have significantly increased scar area, increased apoptosis, decreased capillary density, and increased myocyte cross-section area, confirming echo findings. Analysis of signal transduction 2 days after ligation in AMD and PBS groups showed AKT signaling to be attenuated with no changes in ERK or GSK3beta phosphorylation. Recruitment of ckitpos cardiac progenitors (CPCs) to the risk region after MI was increased in AMD treated mice. ckitpos CPCs were CD34neg and CD45neg. In conclusion, these results suggest SDF1-CXCR4 signaling is necessary for the response to myocardial injury and that AKT signaling may play a significant role in this response. The results also demonstrate that recruitment of CPCs in response to injury require SDF1-CXCR4 signaling to mitigate the extent of injury.