Abstract 16253: SDF-1 Over-Expression Can Correct Adverse Myocardial Repair Associated With Diabetes
Introduction: We have previously demonstrated the importance of the stromal cell-derived factor (SDF):CXCR4 axis in myocardial repair, and that mesenchymal stem cell (MSC) repair following acute myocardial infarction (AMI) is due to SDF-1 secretion.
Hypothesis: Over-expression of SDF-1 is necessary to correct the abnormal post-AMI myocardial repair in diabetes.
Methods: MSC isolated from GFP transgenic mice were induced to overexpress SDF-1 via a lentivirus encoding SDF-1 and SDF-1 levels in control and SDF-1-overexpressing MSC were quantified using ELISA. Lentivirus transfection increased MSC SDF-1 expression by 235%. Acute myocardial infarction (AMI) via left anterior descending (LAD) coronary artery ligation was induced in 12- week old control and db/db mice. Mice were randomly selected to receive injection of saline or 200k control or SDF-1-overexpressing MSC immediately after LAD ligation. Serial echocardiography was used to assess cardiac function. SDF-1 and CXCR4 mRNA expression in the infarct zone of db/db mice and control mice were quantified by qPCR 1 hour, 1, 3 and 5 days after LAD ligation.
Results: Compared to control mice, there is an 82% decrease SDF-1 and 233% increase in CXCR4 expression in db/db mice at baseline. Following LAD ligation, SDF-1 levels remained low in db/db mice at -62%, -92% and -44% of control levels at 1 hour, 1 day and 3 days post-AMI, respectively, compared with control mice. Similarly, CXCR4 levels remained elevated in db/db mice at 188% and 52% of control levels at 1 hour and 5 days post-AMI. The infusion of control MSC led to a significant improvement in ejection fraction in control mice (89%, P=0.01) but not in db/db mice (33%, p=0.2) 21 days after AMI. The infusion of SDF-1-overexpressing MSC led to a significant improvement in ejection fraction in both control mice (114%, P=0.01) and db/db mice (75%, p=0.03) 21 days after AMI.
Conclusion: Our data demonstrate that there is abnormal balance in the SDF-1:CXCR4 axis in diabetes. Our data show that stem cell transplantation is insufficient to overcome this imbalance and improve myocardial repairwithout the over-expression of SDF-1.
Author Disclosures: P. Shamhart: None. M. Kiedrowski: None. M.S. Penn: Research Grant; Significant; Juventas Therapeutics. Ownership Interest; Significant; Juventas Therapeutics. Consultant/Advisory Board; Significant; Juventas Therapeutics. F. Dong: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.