Abstract 359: Disordered Chemokine Expression in Diabetes Following Experimental Myocardial Infarction: Potential Role in Impaired Progenitor Cell Recruitment
BACKGROUND: Impaired collateral vessel formation is thought to contribute to the excessive morbidity in diabetic subjects with ischaemic heart disease where following myocardial infarction (MI) patients with diabetes are twice more likely to develop heart failure than non-diabetic subjects. Since the trafficking of bone marrow derived endothelial progenitor cells is thought to contribute to new vessel formation in ischemia, we postulated that altered chemokine expression may contribute to the impaired angiogenic response in diabetes.
METHODS: Six week old F344 rats were randomized to vehicle or streptozotocin (35mg/kg i.p.) in order to induce diabetes. Once diabetes was confirmed (plasma glucose >15 mM), a total of 40 animals then underwent sham procedure or LAD ligation (MI) at age 10 weeks, and sacrificed at day 0 (sham) and days 1, 2, 4 and 7 post-MI (4 per group). Infarct size was determined by echocardiography 24 hours after ligation. RT q PCR was used to assess mRNA expression levels of SDF-1 and its receptor CXCR4 at each time point, from tissue obtained from the peri-MI zone.
RESULTS: There was no difference in mortality or infarct size between the groups. In control rats an increase in SDF-1 gene expression was apparent at Day 2 post-MI, persisting through Day 7 (p<0.05). In contrast, diabetic rats showed high basal expression (6-fold vs. control, p<0.01) that fell abruptly after MI and remained persistently low throughout the 7-day time course. Diabetes was also associated with increased basal gene expression of CXCR4 (2-fold vs. control, p<0.05). Post-MI, CXCR4 gene expression increased in control rats at each time point, with fold differences up to maximally 3 times at Day 2 (p<0.05 vs. Day 0). In diabetic rats, the level of expression remained high at Day 1, significantly decreased at Day 2 (3-fold vs. non-diabetic, p<0.01) and was comparable to that of non-diabetic rats at days 4 and 7.
CONCLUSIONS: Diabetes was associated with paradoxical alterations in gene expression of both SDF-1 and its receptor CXCR4 with high baseline expression and diminution following an ischemic insult. These findings suggest that disordered chemokine expression may reduce the diabetic heart’s ability to recruit endothelial progenitor cells to sites of ischemic injury.