Abstract 20946: Gene Deletion of Dipeptidyl Peptidase I Prevents Myocyte Apoptosis and Adverse Cardiac Remodeling During the Development of Diabetic Cardiomyopathy
Background: Diabetic cardiomyopathy is characterized by intramyocardial inflammation, cardiomyocyte apoptosis, and cardiac fibrosis. Since inflammatory proteases induce myocyte death and extracellular matrix proteins processing, we hypothesized that increased inflammatory proteases may contribute to the pathophysiological changes observed in the heart during the development of diabetic cardiomyopathy.
Methods and Results: Ten to twelve weeks old mice with deletion of dipeptidyl peptidase I (DPPI), an enzyme involved in the maturation of major neutrophil serine proteases, and wild type (WT) mice controls were injected with streptozotocin (50 mg/kg for 5 days) intraperitoneally and studied after 1, 3 and 8 weeks of induction of diabetes mellitus (DM). Mice with blood sugar above 300 mg/dl were considered diabetic for this study. DPPI deletion had no effect on hyperglycemia. However, neutrophil infiltration and activation of their derived serine proteases, observed at 3 and 8 weeks after streptozotocin (STZ) treatment in WT mice, were completely blunted in DPPI deficient mice. Cardiac hypertrophy and left ventricular dilatation induced at 8 weeks after STZ in WT animals was markedly abrogated in DPPI KO mice. Furthermore, myocyte apoptosis, as quantitated by TUNEL and caspase-3 activity assay, was significantly increased in WT DM at 3 and 8 weeks compared to WT control mice and was markedly attenuated in the DPPI DM compared with DPPI and WT control mice. There was also a significant increase in proinflammatory signaling pathways, p38 MAP kinase and Stat-3 phosphorylation, in WT DM compared to controls and DPPI deletion markedly inhibited these two kinases induced by DM.
Conclusions: These findings suggest that the inflammatory serine proteases are key players in the development of adverse cardiac remodeling observed during diabetic cardiomyopathy. These insights might have useful implications on future studies utilizing neutrophil serine proteases to treat human diabetic cardiomyopathy.
- © 2010 by American Heart Association, Inc.