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

Yochai Birnbaum, Alexander C. Castillo, Jinqiao Qian, Shukuan Ling, Hongmei Ye, Jose R. Perez-Polo, Mandeep Bajaj, Yumei Ye

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20 Citations (Scopus)

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 (p0.001). 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 Ser133 P-CREB, Ser523 P-5-lipoxygenase, Ser473P-Akt and Ser633 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 nondiabeticmice.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.

Original languageEnglish (US)
Pages (from-to)445-456
Number of pages12
JournalCardiovascular Drugs and Therapy
Volume26
Issue number6
DOIs
StatePublished - Dec 2012

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Type 3 Cyclic Nucleotide Phosphodiesterases
Type 2 Diabetes Mellitus
Arachidonate 5-Lipoxygenase
MK0626
cilostazol
PTEN Phosphohydrolase
Dipeptidyl-Peptidase IV Inhibitors
Coronary Occlusion

Keywords

  • CAMP-protein kinase A
  • Diabetes mellitus
  • Dipeptidyl-peptidase-4
  • Infarct size
  • Ischemia
  • Phosphodiesterase-III inhibitor
  • PTEN
  • Reperfusion

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Cardiology and Cardiovascular Medicine
  • Pharmacology

Cite this

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. / Birnbaum, Yochai; Castillo, Alexander C.; Qian, Jinqiao; Ling, Shukuan; Ye, Hongmei; Perez-Polo, Jose R.; Bajaj, Mandeep; Ye, Yumei.

In: Cardiovascular Drugs and Therapy, Vol. 26, No. 6, 12.2012, p. 445-456.

Research output: Contribution to journalArticle

Birnbaum, Yochai ; Castillo, Alexander C. ; Qian, Jinqiao ; Ling, Shukuan ; Ye, Hongmei ; Perez-Polo, Jose R. ; Bajaj, Mandeep ; Ye, Yumei. / 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. In: Cardiovascular Drugs and Therapy. 2012 ; Vol. 26, No. 6. pp. 445-456.
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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 (p0.001). 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 Ser133 P-CREB, Ser523 P-5-lipoxygenase, Ser473P-Akt and Ser633 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 nondiabeticmice.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.",
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T1 - 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

AU - Birnbaum, Yochai

AU - Castillo, Alexander C.

AU - Qian, Jinqiao

AU - Ling, Shukuan

AU - Ye, Hongmei

AU - Perez-Polo, Jose R.

AU - Bajaj, Mandeep

AU - Ye, Yumei

PY - 2012/12

Y1 - 2012/12

N2 - 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 (p0.001). 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 Ser133 P-CREB, Ser523 P-5-lipoxygenase, Ser473P-Akt and Ser633 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 nondiabeticmice.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.

AB - 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 (p0.001). 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 Ser133 P-CREB, Ser523 P-5-lipoxygenase, Ser473P-Akt and Ser633 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 nondiabeticmice.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.

KW - CAMP-protein kinase A

KW - Diabetes mellitus

KW - Dipeptidyl-peptidase-4

KW - Infarct size

KW - Ischemia

KW - Phosphodiesterase-III inhibitor

KW - PTEN

KW - Reperfusion

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