Pharmacological inhibition of PTEN limits myocardial infarct size and improves left ventricular function postinfarction.

Abstract

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
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 298 Issue 4 Pg. H1198-208 (Apr 2010) ISSN: 1522-1539 [Electronic] United States
• PMID: 20097771 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Vanadium Compounds
• bcl-2-Associated X Protein
• bisperoxovanadium
• Nitric Oxide Synthase Type III
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• PTEN Phosphohydrolase
• Pten protein, rat
• Caspase 3

Topics

• 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)