Abstract 15747: Lack Of Serine Exoprotease Dipeptidyl Peptidase-4 Activity Antagonizes Pressure-overload-induced Systolic Dysfunction Predominantly By Glucagon-like Peptide-1/camp Axis.
RATIONALE Dipeptidyl peptidase-4 (DPP4) is a serine exoprotease that degradates SDF-1α and glucagon-like peptide-1 (GLP-1). GLP-1 enhances myocardial contractility and DPP-4 inhibition improves cardiac remodeling after myocardial infarction in rodent models. However, it remains unclear whether the lack of DPP4 may intervene the pressure-overload heart failure.
METHODS & RESULTS Male spontaneous DPP4-null rats (10 wk old) and age-matched DPP4-positive counterparts were allocated into 2 groups: control (DP(-) and DP(+)) and transaortic constriction-induced pressure-overload heart failure (DP(-)/TAC and DP(+)/TAC). Echocardiography revealed the impaired systolic function (EF=53.8%) and prolonged mitral deceleration time in DP(+)/TAC (42.0±7.3 msec), those were restored in DP(-)/TAC (EF=74.3%, Dct= 34.0±1.2msec). Histological analysis revealed increases in interstitial fibrosis and tissue hypoxia detected by pimonidazole in DP(+)/TAC(5 fold increase vs DP(+)). Coronary capillary density was reduced and cardiomyocyte size was increased in DP(+)/TAC. Cardiac HIF-1α level was elevated in DP(+)/TAC, which were restored in DP(-)/TAC. Cardiac SDF-1α level was increased both in DP(+)/TAC and DP(-)/TAC (Fig.1A). GLP-1 level was reduced in DP(+)/TAC heart, which was restored in DP(-)/TAC (Fig.1B). Cyclic AMP concentration in cardiac extract obtained from DP(+)/TAC was reduced and DP(-)/TAC exhibited no decline in cyclic AMP level. Administration of exendin-4 (a GLP-1 receptor agonist, 24 nmole/kg/day for 40days) restored the systolic dysfunction in DP(+)/TAC with concomitant elevation of cyclic AMP without affecting cardiac SDF-1α level nor capillary density.
CONCLUSION Lack of DPP4 activity ameliorates pressure-overload heart failure. GLP-1 predominantly restores pressure-overload heart failure through cAMP-mediated mechanisms independently from the SDF-1α-mediated coronary angiogenesis.
- © 2011 by American Heart Association, Inc.