title: Phosphodiesterase III inhibition increases cAMP levels and augments the infarct size limiting effect of a DPP-4 inhibitor in mice with type-2 diabetes mellitus.
abstract: OBJECTIVE
  We assessed whether phosphodiesterase-III inhibition with cilostazol (Cil) augments the infarct size (IS)-limiting effects of MK0626 (MK), a dipeptidyl-peptidase-4 (DPP4) inhibitor, by increasing intracellular cAMP in mice with type-2 diabetes.
  
  
  METHODS
  Db/Db mice received 3-day MK (0, 1, 2 or 3 mg/kg/d) with or without Cil (15 mg/kg/d) by oral gavage and were subjected to 30 min coronary artery occlusion and 24 h reperfusion.
  
  
  RESULTS
  Cil and MK at 2 and 3 mg/kg/d significantly reduced IS. Cil and MK had additive effects at all three MK doses. IS was the smallest in the MK-3+Cil. MK in a dose dependent manner and Cil increased cAMP levels (p < 0.001). cAMP levels were higher in the combination groups at all MK doses. MK-2 and Cil increased PKA activity when given alone; however, PKA activity was significantly higher in the MK-2+Cil group than in the other groups. Both MK-2 and Cil increased myocardial levels of Ser(133) P-CREB, Ser(523) P-5-lipoxygenase, Ser(473)P-Akt and Ser(633) P-eNOS. These levels were significantly higher in the MK-2+Cil group. Myocardial PTEN (Phosphatase and tensin homolog on chromosome ten) levels were significantly higher in the Db/Db mice compared to nondiabetic mice. MK-2 and Cil normalized PTEN levels. PTEN levels tended to be lower in the combination group than in the MK and Cil alone groups.
  
  
  CONCLUSIONS
  MK and Cil have additive IS-limiting effects in diabetic mice. The additive effects are associated with an increase in myocardial cAMP levels and PKA activity with downstream phosphorylation of Akt, eNOS, 5-lipoxygenase and CREB and downregulation of PTEN expression.
authors.affiliation: The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555, USA.
authors.forename: Yochai
authors.initials: Y
authors.lastname: Birnbaum
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Castillo
authors.forename: Jinqiao
authors.initials: J
authors.lastname: Qian
authors.forename: Shukuan
authors.initials: S
authors.lastname: Ling
authors.forename: Hongmei
authors.initials: H
authors.lastname: Ye
authors.forename: Jose R
authors.initials: JR
authors.lastname: Perez-Polo
authors.forename: Mandeep
authors.initials: M
authors.lastname: Bajaj
authors.forename: Yumei
authors.initials: Y
authors.lastname: Ye
mesh_terms: D000818:Animals; D001786:Blood Glucose; D000077407:Cilostazol; D000242:Cyclic AMP / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D015151:Immunoblotting; D008055:Lipids / Q000097:blood; D044045:Lipoxins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009203:Myocardial Infarction / Q000188:drug therapy*; D009206:Myocardium / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D058987:Phosphodiesterase 3 Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D013777:Tetrazoles / Q000494:pharmacology*; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D000077407:Cilostazol; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D052216:Glucagon-Like Peptide 1; D006442:Glycated Hemoglobin; D008055:Lipids; D044045:Lipoxins; D008565:Membrane Proteins; D051059:PTEN Phosphohydrolase; D058987:Phosphodiesterase 3 Inhibitors; D013777:Tetrazoles; D014230:Triazoles; C570834:MK0626; C040527:lipoxin A4; C446603:TPTE protein, human