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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• 作者：Yochai Birnbaum (1) (2) (3)
  Alexander C. Castillo (1)
  Jinqiao Qian (1) (4)
  Shukuan Ling (1)
  Hongmei Ye (5)
  Jose R. Perez-Polo (1)
  Mandeep Bajaj (6)
  Yumei Ye (1)
  
• 关键词：Diabetes mellitus ; cAMP ; protein kinase A ; Phosphodiesterase ; III inhibitor ; Infarct size ; Ischemia ; Reperfusion ; PTEN ; Dipeptidyl ; peptidase ; 4
• 刊名：Cardiovascular Drugs and Therapy
• 出版年：2012
• 出版时间：December 2012
• 年：2012
• 卷：26
• 期：6
• 页码：445-456
• 全文大小：480KB
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• 作者单位：Yochai Birnbaum (1) (2) (3)
  Alexander C. Castillo (1)
  Jinqiao Qian (1) (4)
  Shukuan Ling (1)
  Hongmei Ye (5)
  Jose R. Perez-Polo (1)
  Mandeep Bajaj (6)
  Yumei Ye (1)
  
  1. The Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX, 77555, USA
  2. The Section of Cardiology, Baylor College of Medicine, Houston, TX, USA
  3. Texas Heart Institute, St. Luke Episcopal Hospital, Houston, TX, USA
  4. Department of Anesthesiology, the First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
  5. Laboratory of Space Medicine Fundamentals and Application, China Astronaut Research and Training Center, Beijing, China
  6. The Section of Endocrinology, Baylor College of Medicine, Houston, TX, USA
  
• ISSN：1573-7241

文摘

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-lt;-.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.