title: Phosphodiesterase-3 inhibition augments the myocardial infarct size-limiting effects of exenatide in mice with type 2 diabetes.
abstract: Glucagon-like peptide (GLP)-1 receptor activation increases intracellular cAMP with downstream activation of PKA. Cilostazol (CIL), a phosphodiesterase-3 inhibitor, prevents cAMP degradation. We assessed whether CIL amplifies the exenatide (EX)-induced increase in myocardial cAMP levels and PKA activity and augments the infarct size (IS)-limiting effects of EX in db/db mice. Mice fed a Western diet received oral CIL (10 mg/kg) or vehicle by oral gavage 24 h before surgery. One hour before surgery, mice received EX (1 μg/kg sc) or vehicle. Additional mice received H-89, a PKA inhibitor, alone or with CIL + EX. Mice underwent 30 min of coronary artery occlusion and 24 h of reperfusion. Both EX and CIL increased myocardial cAMP levels and PKA activity. Levels were significantly higher in the EX + CIL group. Both EX and CIL reduced IS. IS was the smallest in the CIL + EX group. H-89 completely blocked the IS-limiting effects of EX + CIL. EX + CIL decreased phosphatase and tensin homolog on chromosome 10 upregulation and increased Akt and ERK1/2 phosphorylation after ischemia-reperfusion. These effects were blocked by H-89. In conclusion, EX and CIL have additive effects on IS limitation in diabetic mice. The additive effects are related to cAMP-induced PKA activation, as H-89 blocked the protective effect of CIL + EX.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Yumei
authors.initials: Y
authors.lastname: Ye
authors.forename: Jinqiao
authors.initials: J
authors.lastname: Qian
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Castillo
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: Yochai
authors.initials: Y
authors.lastname: Birnbaum
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D015153:Blotting, Western; D002784:Cholesterol / Q000097:blood; D000077407:Cilostazol; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D006442:Glycated Hemoglobin / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology; D044045:Lipoxins / Q000378:metabolism; D008297:Male; D051379:Mice; D009203:Myocardial Infarction / Q000097:blood / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018027:Receptors, Glucagon / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood; D015854:Up-Regulation; D014688:Venoms / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D002784:Cholesterol; D000077407:Cilostazol; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D007546:Isoquinolines; D044045:Lipoxins; D051059:PTEN Phosphohydrolase; D010455:Peptides; D058987:Phosphodiesterase 3 Inhibitors; D047428:Protein Kinase Inhibitors; D018027:Receptors, Glucagon; D013449:Sulfonamides; D013777:Tetrazoles; D014280:Triglycerides; D014688:Venoms; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C517652:hemoglobin A1c protein, human; C040527:lipoxin A4; C487757:Pten protein, mouse; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide