Document Detail


Pharmacological inhibition of PTEN limits myocardial infarct size and improves left ventricular function postinfarction.
MedLine Citation:
PMID:  20097771     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Phosphoinositide 3-kinase (PI3K) mediates myocardium protective signaling through phosphorylation of phosphatidylinositol (Ptdins) to produce Ptdins(3,4,5)P(3). Lipid phosphatase and tensin homolog on chromosome 10 (PTEN) antagonizes PI3K activity by dephosphorylating Ptdins(3,4,5)P(3); therefore, the inhibition of PTEN enhances PI3K/Akt signaling and could prevent myocardium from ischemia-reperfusion (I/R) injury. Here we studied 1) whether the pharmacological inhibition of PTEN by bisperoxovanadium molecules [BpV(HOpic)] attenuates simulated I/R (SIR) injury in vitro and 2) whether the administration of BpV(HOpic) either before or after ischemia limits myocardial infarct size (IS) and ameliorates cardiodysfunction caused by infarction. First, adult rat cardiomyocytes were treated with or without BpV(HOpic) and then exposure to SIR. Second, anesthetized rats received BpV(HOpic) either before or after ischemia. IS was assessed at 4 h reperfusion, and left ventricular function was evaluated by echocardiography at 28 days postreperfusion. As a result, BpV(HOpic) decreased cell death, improved 3-[4,5-yl]-2,5-diphenyltetrazolium bromide (MTT) viability, and reduced apoptosis in cells exposed to SIR. These protective effects of BpV(HOpic) are associated with increased phospho-Akt and the repression of caspase-3 activity. Second, the administration of BpV(HOpic) significantly reduced IS and suppressed caspase-3 activity following I/R injury and consequentially improved cardiac function at 28 day postinfarction. These beneficial effects of BpV(HOpic) are attributed to increases in myocardial levels of phosphorylation of Akt/endothelial nitric oxide synthase (eNOS), ERK-1/2, and calcium-dependent nitric oxide synthase activity. In conclusion, the pharmacological inhibition of PTEN protects against I/R injury through the upregulation of the PI3K/Akt/eNOS/ERK prosurvival pathway, suggesting a new therapeutic strategy to combat I/R injury.
Authors:
Kyle T Keyes; Jing Xu; Bo Long; Congfang Zhang; Zhaoyong Hu; Yumei Ye
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-01-22
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 Apr 
Date Detail:
Created Date:  2010-03-22     Completed Date:  2010-04-12     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:  H1198-208     Citation Subset:  IM    
Affiliation:
Dept. of Biochemistry and Molecular Biology, Univ. of Texas Medical Branch, Galveston, 77555, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Caspase 3 / metabolism
Cells, Cultured
Disease Models, Animal
Enzyme Inhibitors / therapeutic use*
Extracellular Signal-Regulated MAP Kinases / metabolism
Male
Myocardial Infarction / drug therapy*,  metabolism,  pathology
Myocardial Reperfusion Injury / metabolism,  pathology,  prevention & control
Myocytes, Cardiac / metabolism,  pathology
Nitric Oxide Synthase Type III / metabolism
PTEN Phosphohydrolase / antagonists & inhibitors*,  metabolism
Proto-Oncogene Proteins c-akt / metabolism
Rats
Rats, Sprague-Dawley
Vanadium Compounds / therapeutic use*
Ventricular Dysfunction, Left / drug therapy*,  physiopathology
bcl-2-Associated X Protein / metabolism
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Vanadium Compounds; 0/bcl-2-Associated X Protein; 0/bisperoxovanadium; EC 1.14.13.39/Nitric Oxide Synthase Type III; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases; EC 3.1.3.48/Pten protein, rat; EC 3.1.3.67/PTEN Phosphohydrolase; EC 3.4.22.-/Caspase 3

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


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