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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

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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 (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 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 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.

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Acknowledgments

Author contributions

Yumei Ye: Research design, Research data, wrote the manuscript:

Jinqiao Qian: Research data, analysis, edited manuscript

Alexander C. Castillo: Research data and analysis, edited manuscript

Shukuan Ling: Research data and analysis, edited manuscript

Hongmei Ye: Dada analysis and edited manuscript

Jose R. Perez-Polo: Data analysis, problem solving, edited manuscript

Mandeep Bajaj: Data analysis, edited manuscript

Yochai Birnbaum: Research design, data analysis, statistics, graphs, wrote and edited manuscript

Guarantor name: Yochai Birnbaum, MD

Funding support

Merck Pharmaceuticals, Inc.

Disclosures

Yumei Ye: Research grants from Amylin; Merck; Takeda; Roche, Boehringer Ingelheim

Jinqiao Qian: None

Alexander C. Castillo: None

Shukuan Ling: None

Hongmei Ye: None

Jose R. Perez-Polo: None

Mandeep Bajaj: Research grants from Takeda, Amylin, Eli Lilly, Bristol-Myers Squibb, and Astra Zenica; honoraria for speaking from Takeda, Eli Lilly, Boehringer Ingelheim, and Sanofi-Aventis; and has served as a consultant to Takeda and Sanofi-Aventis

Yochai Birnbaum: Research grants from Amylin; Merck; Takeda; Roche, Boehringer Ingelheim.

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Correspondence to Yumei Ye.

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Yochai Birnbaum and Alexander C. Castillo equally contributed to the manuscript.

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Birnbaum, Y., Castillo, A.C., Qian, J. et al. 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 26, 445–456 (2012). https://doi.org/10.1007/s10557-012-6409-x

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  • DOI: https://doi.org/10.1007/s10557-012-6409-x

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