Abstract 14305: Cardiac Dipeptidylpeptidase4 is Reduced in Response to Hypoxia and Enhances Compensatory Angiogenesis in Pressure-Overloaded Heart
[INTRODUCTION] Maladapitive cardiac hypertrophy is associated with comorbid hypoxia. We have reported that cardiac dipeptidylpeptidase-4 (DPP4) is localized in capillary endothelium and its activation causes cardiac remodeling in diabetes. However, the role of DPP4 in the cardiac remodeling induced by nondiabetic causes remains unclear.
[HYPOTHESIS] We assessed the following hypotheses: #1: DPP4 inhibition may ameliorate cardiac remodeling induced by pressure overload. #2.hypoxia may modulate the endothelial DPP4 expression and activity.
[METHODS] Pressure overload was induced by transaortic constriction (TAC) in rodents with and without DPP4 inhibition [DP(+) and DP(-), respectively] generated by genetic mutation (F344/DuCrlCrlj) and pharmacological inhibition (10mg/kg/day alogliptin). Cultured microvascular endothelial cells (HMVEC) were exposed to hypoxia (24 hours).
[RESULTS] Cardiac DPP4 activity was decreased in DP(+)-TAC (0.54±0.05-fold versus sham-control, n=8). The level of cardiac SDF1α, one of the DPP4 substrates, was increased (1.84±0.9-fold versus sham-control) in DP4(+)-TAC. The cardiac Akt/eNOS activities were enhanced in DP4(+)-TAC. Immunohistochemistry revealed that DP4(+)-TAC heart exhibited hypoxia without decline in capillary density. In HMVEC, hypoxia reduced the levels of DPP4 (0.71±0.04-fold versus normoxic-counterpart). On the contrary, the circulating DPP4 activity of DP4(+)-TAC was elevated (1.37±0.05-fold versus sham-control) with concomitant reduction of circulating GLP-1 level (0.76±0.05-fold versus sham-control). Echocardiography revealed that both genetic and pharmacological DPP4-inhibitions ameliorated systolic and diastolic dysfunction observed in TAC. Cardiac cyclic AMP (cAMP) concentration and protein kinase A (PKA) activity were decreased in DP4(+)-TAC. The DPP4 inhibition reversed the decline in the GLP-1/cAMP/PKA axis.
[CONCLUSIONS] DPP4 inhibition ameliorates pressure-overload-induced heart failure through the GLP-1/cAMP/PKA axis which is distinct from the case observed in diabetic heart. Cardiac DPP4 is reduced in response to myocardial hypoxia and enhances compensatory angiogenesis via increase in SDF1α.
- © 2012 by American Heart Association, Inc.