Inflammatory Serine Proteases Play a Critical Role in the Early Pathogenesis of Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DCM) is characterized by structural and functional alterations that can lead to heart failure. Several mechanisms are known to be involved in the pathogenesis of DCM, however, the molecular mechanism that links inflammation to DCM is incompletely understood. To learn about this mechanism, we investigated the role of inflammatory serine proteases (ISPs) during the development of DCM.Eight 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 (50 mg/kg for 5 days intraperitoneally) and studied after 4, 8, 16, and 20 week after induction of type 1 diabetes mellitus (T1DM). Induction of diabetes was followed by echocardiographic measurements, glycemic and hemoglobulin A1c profiling, immunoblot, qPCR, enzyme activity assays, and immunohistochemistry (IHC) analysis of DPPI, ISPs, and inflammatory markers. Fibrosis was determined from left ventricular heart by Serius Red staining and qPCR. Apoptosis was determined by TUNEL assay and immunoblot analysis.In the diabetic WT mice, DPPI expression increased along with ISP activation, and DPPI accumulated abundantly in the left ventricle mainly from infiltrating neutrophils. In diabetic DPPI-knockout (DPPI-KO) mice, significantly decreased activation of ISPs, myocyte apoptosis, fibrosis, and cardiac function was improved compared to diabetic WT mice. In addition, DPPI-KO mice showed a decrease in overall inflammatory status mediated by diabetes induction which was manifested by decreased production of pro-inflammatory cytokines like TNF-α, IL-1β and IL-6.This study elucidates a novel role of ISPs in potentiating the immunological responses that lead to the pathogenesis of DCM in T1DM. To the best of our knowledge, this is the first study to report that DPPI expression and activation promotes the inflammation that enhances myocyte apoptosis and contributes to the adverse cardiac remodeling that subsequently leads to DCM.