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

Cardiovasc Drugs Ther. 2012 Dec;26(6):445-56. doi: 10.1007/s10557-012-6409-x.

Abstract

Purpose: 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose
  • Cilostazol
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Diabetes Mellitus, Type 2 / metabolism*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Therapy, Combination
  • Glucagon-Like Peptide 1
  • Glycated Hemoglobin A
  • Immunoblotting
  • Lipids / blood
  • Lipoxins / metabolism
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Myocardial Infarction / drug therapy*
  • Myocardium / metabolism
  • PTEN Phosphohydrolase / metabolism
  • Phosphodiesterase 3 Inhibitors / administration & dosage
  • Phosphodiesterase 3 Inhibitors / pharmacology*
  • Tetrazoles / pharmacology*
  • Triazoles / administration & dosage
  • Triazoles / pharmacology*

Substances

  • Blood Glucose
  • Glycated Hemoglobin A
  • Lipids
  • Lipoxins
  • MK0626
  • Membrane Proteins
  • Phosphodiesterase 3 Inhibitors
  • Tetrazoles
  • Triazoles
  • lipoxin A4
  • Glucagon-Like Peptide 1
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • TPTE protein, human
  • PTEN Phosphohydrolase
  • Cilostazol