title: 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.
abstract: 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.
  
  
  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; 0.86 ± 0.10 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.
authors.affiliation: From the Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Morihiko
authors.initials: M
authors.lastname: Aoyama
authors.affiliation: From the Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Haruya
authors.initials: H
authors.lastname: Kawase
authors.forename: Yasuko K
authors.initials: YK
authors.lastname: Bando
authors.forename: Akio
authors.initials: A
authors.lastname: Monji
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D052216:Glucagon-Like Peptide 1 / Q000037:antagonists & inhibitors / Q000097:blood*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006333:Heart Failure / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010446:Peptide Fragments / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014498:Uracil / Q000031:analogs & derivatives* / Q000494:pharmacology; D020257:Ventricular Remodeling / Q000187:drug effects*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D010446:Peptide Fragments; D010880:Piperidines; D019253:Proto-Oncogene Proteins c-bcl-2; C052617:Bcl2 protein, mouse; C083773:exendin (9-39); D014498:Uracil; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; D020827:rap1 GTP-Binding Proteins; C520853:alogliptin
keywords: Rap1 GTP-binding proteins; apoptosis; cyclic AMP-dependent protein kinases; heart failure; incretins; pharmacology; signal transduction