The myocardial infarct size-limiting effect of sitagliptin is PKA-dependent, whereas the protective effect of pioglitazone is partially dependent on PKA.
Pioglitazone (PIO) and glucagon-like peptide-1 (GLP-1) analogs limit infarct size (IS) in experimental models. The effects of the dipeptidyl-peptidase-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 A(2) and cyclooxygenase-2 activity. Accordingly, 6-keto-PGF(1alpha) and 15-deoxy-PGJ(2) increased by PIO but not SIT. In contrast, SIT, and to a lesser extent PIO, increased 15-epi-lipoxin A(4) levels. H-89 completely blocked the effect of SIT and PIO on 15-epi-lipoxin A(4) 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.
Ye
Yumei
Y
John S. Dunn Chair in Cardiology Research and Education, Department of Medicine, Section of Cardiology, Baylor College of Medicine, 1709 Dryden Road, Houston, TX 77030, USA.
Keyes
Kyle T
KT
Zhang
Congfang
C
Perez-Polo
Jose R
JR
Lin
Yu
Y
Birnbaum
Yochai
Y
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D003470:Culture Media; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D015777:Eicosanoids / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000473:pathology; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D066298:In Vitro Techniques; D051379:Mice; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D054467:Phospholipases A2 / Q000378:metabolism; D000077205:Pioglitazone; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D020011:Protective Agents / Q000627:therapeutic use; D011719:Pyrazines / Q000627:therapeutic use*; D000068900:Sitagliptin Phosphate; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014230:Triazoles / Q000627:therapeutic use*
D001786:Blood Glucose; D003470:Culture Media; D054873:Dipeptidyl-Peptidase IV Inhibitors; D015777:Eicosanoids; D007004:Hypoglycemic Agents; D020011:Protective Agents; D011719:Pyrazines; D045162:Thiazolidinediones; D014230:Triazoles; D052216:Glucagon-Like Peptide 1; D000242:Cyclic AMP; D011451:Prostaglandin-Endoperoxide Synthases; D017868:Cyclic AMP-Dependent Protein Kinases; D054467:Phospholipases A2; D000068900:Sitagliptin Phosphate; D000077205:Pioglitazone