title: Dipeptidyl peptidase-4 inhibition improves cardiac function in experimental myocardial infarction: Role of stromal cell-derived factor-1α.
abstract: BACKGROUND
  In addition to degrading glucagon-like peptide-1 (GLP-1), dipeptidyl peptidase-4 (DPP-4) inactivates several chemokines, including stromal cell-derived factor-1α (SDF-1α), a pro-angiogenic and cardiomyocyte protective protein. We hypothesized that DPP-4 inhibition may confer benefit following myocardial infarction (MI) in the diabetic setting as a consequence of enhanced SDF-1α availability rather than potentiating GLP-1. To test this we compared the effects of saxagliptin with those of liraglutide and used the SDF-1α receptor (CXCR4) antagonist plerixafor.
  
  
  METHODS
  Studies were conducted in streptozotocin-diabetic rats. Rats were randomized to receive saxagliptin (10 mg/kg per day), liraglutide (0.2 mg/kg, s.c., b.i.d.), plerixafor (1 mg/kg per day, s.c.), saxagliptin plus plerixafor or vehicle (1% phosphate-buffered saline). Two weeks later, rats underwent experimental MI, with cardiac function examined 4 weeks after MI.
  
  
  RESULTS
  Glycemic control and MI size were similar in all groups. Four weeks after MI, mortality was reduced in saxagliptin-treated rats compared with vehicle treatment (P < 0.05). Furthermore, rats receiving saxagliptin had improved cardiac function compared with vehicle-treated rats (P < 0.05). Antagonism of CXCR4 prevented the improvement in cardiac function in saxagliptin-treated rats and was associated with increased mortality (P < 0.05).
  
  
  CONCLUSIONS
  Saxagliptin-mediated DPP-4 inhibition, but not liraglutide-mediated GLP-1R agonism, improved cardiac function after MI independent of glucose lowering. These findings suggest that non-GLP-1 actions of DPP-4 inhibition, such as SDF-1α potentiation, mediate biological effects.
authors.affiliation: Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Kim A
authors.initials: KA
authors.lastname: Connelly
authors.affiliation: Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Andrew
authors.initials: A
authors.lastname: Advani
authors.affiliation: Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Advani
authors.affiliation: Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Golam
authors.initials: G
authors.lastname: Kabir
authors.affiliation: Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Armin
authors.initials: A
authors.lastname: Abadeh
authors.affiliation: Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Desjardins
authors.affiliation: Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Melissa
authors.initials: M
authors.lastname: Mitchell
authors.affiliation: Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Kerri
authors.initials: K
authors.lastname: Thai
authors.affiliation: Keenan Research Centre for Biomedical Science of St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Gilbert
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D001596:Benzylamines; D006328:Cardiac Catheterization; D054377:Chemokine CXCL12 / Q000378:metabolism*; D000080027:Cyclams; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000503:physiopathology*; D004151:Dipeptides / Q000627:therapeutic use*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D004452:Echocardiography; D006571:Heterocyclic Compounds / Q000627:therapeutic use; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D000069450:Liraglutide / Q000627:therapeutic use; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology*; D051381:Rats; D011916:Rats, Inbred F344; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; D000067757:Glucagon-Like Peptide-1 Receptor
chemical_list: D000218:Adamantane; D001596:Benzylamines; D054377:Chemokine CXCL12; D000080027:Cyclams; D004151:Dipeptides; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006571:Heterocyclic Compounds; D007004:Hypoglycemic Agents; D000069450:Liraglutide; D000097789:Glucagon-Like Peptide-1 Receptor Agonists; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; C502994:saxagliptin; C088327:plerixafor
keywords: diastolic dysfunction; dipeptidyl peptidase-4; microvasculature; myocardial infarction; stromal cell-derived factor-1α; 二肽基肽酶-4; 微血管; 心肌梗死; 舒张功能障碍; 间质细胞衍生因子-1α