Abstract 15514: Activation of Serine Exoprotease Dipeptidyl Peptidase-4 Impairs Coronary Angiogenesis by Degradation of Cardiac SDF1alfa Leading to Maladaptive Cardiac Remodeling in Diabetes.
RATIONALE Dipeptidyl peptidase-4 (DPP4/CD26) is a exoprotease that degradates chemokines including SDF-1α. DPP4 inhibition has been demonstrated to improve mortality and cardiac remodeling after myocardial infarction in rodent models. However, precise distribution of DPP4 in heart and its roles in non-ischemic myocardial remodeling remain unclear.
METHODS & RESULTS Male spontaneous DPP4-null rats (19 wk old) and age-matched syngeneic DPP4-positive counterparts were allocated into 2 groups (n=8): control (DP(-)/c and DP(+)/c) and streptozotocin-induced diabetes (DP(-)/DM and DP(+)/DM). Confocal microscopy of cardiac sections demonstrated that the CD26-positive areas were co-localized with CD31-positive areas, those were absent in the endothelium of arteriole, venules and lymphatic vessels. In DP(+)/DM, circulating and cardiac DPP4 activities were elevated. Histological analysis revealed cardiac fibrosis (1.9± 0.1 fold vs DP(+)) and tissue hypoxia detected by pimonidazole (hypoxyprobe-1™) (7.7 fold increase) were increased in DP(+)/DM. Coronary capillary density (-2.02±0.47 fold vs DP(+)) and cardiomyocyte size were lowered in DP(+)/DM. Cardiac SDF-1α level was lower in DP(+)/DM, however, the level of vascular endothelial growth factor A remained unchanged (Fig.1). Echocardiography revealed prolonged mitral deceleration time in DP(+)/DM (in msec; 43.8±7.3 versus 34.3±1.2 for DP(+)/c). There was no changes in SDF-1α level, capillary density, cardiomyocyte size, tissue hypoxia, and fibrosis of DP(-)/DM heart, of which diastolic function detected by echocardiography exhibited within normal limits.
CONCLUSION The present study demonstrates that cardiac DPP4 expression is limited to capillary endothelium and the DPP4-mediated SDF1α degradation impairs coronary angiogenesis which contributes to maladaptive cardiac remodeling and diastolic dysfunction in diabetes.
- © 2011 by American Heart Association, Inc.