Abstract 14321: Inflammatory Serine Proteases Regulate Insulin Signaling and Myocyte Death During the Development of Diabetic Cardiomyopathy
Background: Diabetic cardiomyopathy (DCM) is typified by alterations in cardiac morphology and function, independent of hypertension or coronary disease. DCM is characterized by intramyocardial inflammation, cardiomyocyte apoptosis and cardiac fibrosis. The molecular mechanism that links inflammation to DCM is incompletely understood. This study investigates the role of inflammatory cell-derived serine proteases (ISPs) on the development of DCM.
Methods and Results: Ten weeks old mice with deletion of dipeptidyl peptidase I (DPPI), an enzyme involved in the maturation of major ISPs, and wild type (WT) mice controls were injected with streptozotocin (STZ, 50 mg/kg for 5 days intraperitoneally) and studied after 1, 3 and 8 weeks after induction of diabetes. Induction of diabetes in WT mice resulted in an increase in DPPI expression and activity in hearts compared to shams that correlated with an increase in the activity of several ISPs (cathepsin G (CG), elastase, chymase). DPPI deletion had no effect on hyperglycemic state of the animals. However, DPPI deficiency reduced ISPs activity, attenuated cell apoptosis and improved cardiac function after STZ treatment compared to WT mice. DPPI inhibition also enhanced insulin sensitivity and increased glucose uptake after STZ treatment compared to WT mice, suggesting that ISPs negatively regulate insulin receptor signaling. To delineate the mechanisms involved, we found that treatment of cardiomyocytes with neutrophil-derived protease CG impaired insulin receptor signaling and led to myofibril degeneration and myocyte apoptosis. Incubation of myocytes in hyperglycemic conditions enhanced insulin receptor signaling deterioration and myocyte apoptosis induced by CG.
Conclusion: These data suggest that ISPs are important regulators of insulin receptor signaling and myocyte death and may play an important role in regulating insulin signaling and glucose metabolism during the development of DCM.
- © 2013 by American Heart Association, Inc.