Abstract 1166: Post- Infarct Remodeling is Altered in Diabetes: Role for Receptor for Advanced Glycation End-Products and S100B
BACKGROUND: Diabetes (DM) may modulate the structural and functional consequences of adverse left ventricular (LV) remolding after myocardial infarction (MI). While the importance of Receptor for Advanced Glycation End-products (RAGE) and its ligand, S100B, has been demonstrated in diabetic vascular complications, their role in post-MI LV remodeling in DM remains unexplored.
OBJECTIVES: LV remodeling in diabetic post-MI myocardium, the associated regulation of fibrosis, matrix metalloproteinase (MMP) activity and expression of RAGE/S100B was examined.
METHODS AND RESULTS: DM (glucose, 28±1.2 mmol/L) was induced in mice by streptozotocin (40 mg/kg) injection for 15 weeks followed by coronary artery ligation or sham operation with analysis at 4 weeks post-MI in four experimental groups (Con, DM, MI, and DM+MI). MI+DM resulted in less dilation than MI alone (LV end-diastolic dimension 5.1± 0.02 mm vs. 6.3±0.02 mm, p<0.02, n=10) despite comparable infarct size and impairment of cardiac function assessed echocardiographically. Picrosirius red staining demonstrated greater increase of total LV collagen in DM+MI versus DM and MI (5.7±1 vs. 2.3±0.2 and 2.0±0.1 fold relative to Con, respectively, p<0.05, n=10). Gel zymography demonstrated significantly higher induction of latent and active MMP-2 in MI alone compare to DM+MI (2.4±0.1 and 2.2±0.3 fold vs. 1.3±0.3 and 1.1±0.1 fold relative to Con, respectively, p<0.05, n=10). Apoptosis was increased in DM+MI compare to MI (3.6±0.5 and 2.3±0.3 fold vs. Con, p<0.04, respectively, n=4), but myocyte hypertrophy was not different between two groups. LV RAGE mRNA expression was augmented in DM and DM+MI (4.0±0.6 and 4.9±0.7 fold vs. Con, p<0.004, n=10) to a greater extent than in MI alone (2.6±0.7 fold vs. Con, p<0.004, n=10). S100B mRNA induction was paradoxically greater in MI alone than DM+MI (11.8±2.7 and 4.1±1.3 fold vs. Con, respectively, p<0.004, n=10).
CONCLUSION: DM was accompanied with less dilation and higher apoptosis following MI in association with increased collagen deposition and reduced MMP-2 activity. Increased RAGE expression and interaction with AGE or alternate ligand, S100B, may play an important mechanistic role in LV remodeling in DM via regulation of collagen content and MMP activity.