Phosphodiesterase-3 inhibition augments the myocardial infarct size-limiting effects of exenatide in mice with type 2 diabetes

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

Research output: Contribution to journalArticle

19 Scopus citations

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 ischemiareperfusion. 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.

Original languageEnglish (US)
Pages (from-to)H131-H141
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume304
Issue number1
DOIs
StatePublished - Jan 1 2013

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Keywords

  • Cilostazol
  • Glucagon-like peptide-1
  • Infarct size
  • Phosphatase and tensin homolog on chromosome 10
  • Phosphdiesterase-3 inhibitor
  • Protein kinase A
  • cAMP

ASJC Scopus subject areas

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

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