Document Detail


The myocardial infarct size-limiting effect of sitagliptin is PKA-dependent, whereas the protective effect of pioglitazone is partially dependent on PKA.
MedLine Citation:
PMID:  20207816     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Yumei Ye; Kyle T Keyes; Congfang Zhang; Jose R Perez-Polo; Yu Lin; Yochai Birnbaum
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-03-05
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  298     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-05-05     Completed Date:  2010-05-18     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H1454-65     Citation Subset:  IM    
Affiliation:
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.
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MeSH Terms
Descriptor/Qualifier:
Animals
Blood Glucose / metabolism
Blotting, Western
Body Weight / drug effects
Culture Media
Cyclic AMP / metabolism
Cyclic AMP-Dependent Protein Kinases / physiology*
Dipeptidyl-Peptidase IV Inhibitors / pharmacology*
Eicosanoids / metabolism
Glucagon-Like Peptide 1 / metabolism
Hypertrophy, Left Ventricular / pathology
Hypoglycemic Agents / therapeutic use*
Mice
Myocardial Infarction / drug therapy*,  pathology
Myocardium / metabolism,  pathology
Myocytes, Cardiac / drug effects,  pathology
Organ Size / drug effects
Phospholipases A2 / metabolism
Prostaglandin-Endoperoxide Synthases / metabolism
Protective Agents / therapeutic use
Pyrazines / therapeutic use*
Thiazolidinediones / therapeutic use*
Triazoles / therapeutic use*
Chemical
Reg. No./Substance:
0/Blood Glucose; 0/Culture Media; 0/Dipeptidyl-Peptidase IV Inhibitors; 0/Eicosanoids; 0/Hypoglycemic Agents; 0/Protective Agents; 0/Pyrazines; 0/Thiazolidinediones; 0/Triazoles; 0/sitagliptin; 111025-46-8/pioglitazone; 60-92-4/Cyclic AMP; 89750-14-1/Glucagon-Like Peptide 1; EC 1.14.99.1/Prostaglandin-Endoperoxide Synthases; EC 2.7.11.11/Cyclic AMP-Dependent Protein Kinases; EC 3.1.1.4/Phospholipases A2

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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