Dipeptidyl Peptidase 4 Inhibition Alleviates Shortage of Circulating Glucagon-Like Peptide-1 in Heart Failure and Mitigates Myocardial Remodeling and Apoptosis via the Exchange Protein Directly Activated by Cyclic AMP 1/Ras-Related Protein 1 Axis

作者：Aoyama Morihiko; Kawase Haruya; Bando Yasuko K; Monji Akio; Murohara Toyoaki

来源：Circulation-Heart Failure, 2016, 9(1): e002081.

DOI：10.1161/CIRCHEARTFAILURE.115.002081

• apoptosis
• cyclic AMP-dependent protein kinases
• heart failure
• incretins
• pharmacology
• Rap1 GTP-binding proteins
• signal transduction

Background Ample evidence demonstrates cardiovascular protection by incretin-based therapy using dipeptidyl peptidase 4 inhibitor (DPP4i) and glucagon-like peptide-1 (GLP-1) under either diabetic or nondiabetic condition. Their action on myocardium is mediated by the cyclic AMP (cAMP) signal; however, the pathway remains uncertain. This study was conducted to address the effect of DPP4i/GLP-1/cAMP axis on cardiac dysfunction and remodeling induced by pressure overload (thoracic aortic constriction [TAC]) independently of diabetes mellitus.
Methods and Results DPP4i (alogliptin, 10 mg/kg per day for 4 weeks) prevented TAC-induced contractile dysfunction, remodeling, and apoptosis of myocardium in a GLP-1 receptor antagonist (exendin [9-39])-sensitive fashion. In TAC, circulating level of GLP-1 (in pmol/L; 0.860.10 for TAC versus 2.13 +/- 0.54 for sham control) unexpectedly declined and so did the myocardial cAMP concentration (in pmol/mg protein; 33.0 +/- 1.4 for TAC versus 42.2 +/- 1.5 for sham). Alogliptin restored the decline in the GLP-1/cAMP levels observed in TAC, thereby augmented cAMP signaling effectors (protein kinase A [PKA] and exchange protein directly activated by cAMP 1 [EPAC1]). In vitro assay revealed distinct roles of PKA and EPAC1 in cardiac apoptosis. EPAC1 promoted cardiomyocyte survival via concomitant increase in B cell lymphoma-2 (Bcl-2) expression and activation of small G protein Ras-related protein 1 (Rap1) in a cAMP dose-dependent and PKA-independent fashion.
Conclusions DPP4i restores cardiac remodeling and apoptosis caused by the pathological decline in circulating GLP-1 in response to pressure overload. EPAC1 is essential for cardiomyocyte survival via the cAMP/Rap1 activation independently of PKA.

• 出版日期2016-1