The myocardial infarct size-limiting effect of sitagliptin is PKA-dependent, whereas the protective effect of pioglitazone is partially dependent on PKA

Yumei Ye, Kyle T. Keyes, Congfang Zhang, Jose R. Perez-Polo, Yu Lin, Yochai Birnbaum

Research output: Contribution to journalArticle

130 Scopus citations

Abstract

Pioglitazone (PIO) and glucagon-like peptide-1 (GLP-1) analogs limit infarct size (IS) in experimental models. The effects of the dipeptidylpeptidase-IV inhibitors, which increase the endogenous levels of GLP-1, on myocardial protection, are unknown. We studied whether sitagliptin (SIT) and PIO have additive effects on IS limitation in the mouse. Mice received 3-day or 14-day oral SIT (300 mg·kg-1·day -1), PIO (5 mg·kg-1·day-1), SIT + PIO, or vehicle. In addition, mice received intravenous H-89 [20 mg/kg, a protein kinase A (PKA) inhibitor] or vehicle 1 h before ischemia. Rats underwent 30 min myocardial ischemia and 4 h reperfusion. SIT, PIO, and SIT + PIO for 3 days significantly reduced IS (24.3 ± 2.7, 23.0 ± 0.8, and 14.7 ± 0.9%) compared with controls (46.2 ± 2.8%). H-89 completely blocked the effect of SIT and partially blocked the PIO effect. SIT, but not PIO, increased cAMP levels. PKA activity was increased by PIO and to a greater extent by SIT. PIO, but not SIT, increased cytosolic phospholipase A2 and cyclooxygenase-2 activity. Accordingly, 6-keto-PGF and 15-deoxy-PGJ2 increased by PIO but not SIT. In contrast, SIT, and to a lesser extent PIO, increased 15-epi-lipoxin A4 levels. H-89 completely blocked the effect of SIT and PIO on 15-epi-lipoxin A4 levels. PIO, and to a greater extent SIT, increased endothelial nitric oxide synthase and cAMP response element-binding protein phosphorylation, an effect that was blocked by H-89. With a 14-day pretreatment experiment, IS was 46.4 ± 1.0% in the control group, 16.9 ± 0.6% in SIT (P < 0.001), 19.1 ± 1.1% in PIO (P = 0.014), and 12.9 ± 0.7% in SIT + PIO (P < 0.001). We found that SIT and PIO limit IS using different pathways. The protective effect of SIT is via cAMP-dependent PKA activation, whereas PIO mediates its effects via both PKA-dependent and -independent pathways.

Original languageEnglish (US)
Pages (from-to)H1454-H1465
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume298
Issue number5
DOIs
StatePublished - May 1 2010

    Fingerprint

Keywords

  • Adenosine 3′-5′-cyclic monophosphate
  • Protein kinase A

ASJC Scopus subject areas

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

Cite this