20-HETE increases survival and decreases apoptosis in pulmonary arteries and pulmonary artery endothelial cells. Am J Physiol Heart Circ Physiol 2009 Mar;296(3):H777-86
Date
01/13/2009Pubmed ID
19136601Pubmed Central ID
PMC2660237DOI
10.1152/ajpheart.01087.2008Scopus ID
2-s2.0-64049113217 (requires institutional sign-in at Scopus site) 41 CitationsAbstract
20-Hydroxyeicosatetraenoic acid (20-HETE) is an endogenous cytochrome P-450 product present in vascular smooth muscle and uniquely located in the vascular endothelium of pulmonary arteries (PAs). 20-HETE enhances reactive oxygen species (ROS) production of bovine PA endothelial cells (BPAECs) in an NADPH oxidase-dependent manner and is postulated to promote angiogenesis via activation of this pathway in systemic vascular beds. We tested the capacity of 20-HETE or a stable analog of this compound, 20-hydroxy-eicosa-5(Z),14(Z)-dienoic acid, to enhance survival and protect against apoptosis in BPAECs stressed with serum starvation. 20-HETE produced a concentration-dependent increase in numbers of starved BPAECs and increased 5-bromo-2'-deoxyuridine incorporation. Caspase-3 activity, nuclear fragmentation studies, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays supported protection from apoptosis and enhanced survival of starved BPAECs treated with a single application of 20-HETE. Protection from apoptosis depended on intact NADPH oxidase, phosphatidylinositol 3 (PI3)-kinase, and ROS production. 20-HETE-stimulated ROS generation by BPAECs was blocked by inhibition of PI3-kinase or Akt activity. These data suggest 20-HETE-associated protection from apoptosis in BPAECs required activation of PI3-kinase and Akt and generation of ROS. 20-HETE also protected against apoptosis in BPAECs stressed by lipopolysaccharide, and in mouse PAs exposed to hypoxia reoxygenation ex vivo. In summary, 20-HETE may afford a survival advantage to BPAECs through activation of prosurvival PI3-kinase and Akt pathways, NADPH oxidase activation, and NADPH oxidase-derived superoxide.
Author List
Dhanasekaran A, Bodiga S, Gruenloh S, Gao Y, Dunn L, Falck JR, Buonaccorsi JN, Medhora M, Jacobs ERMESH terms used to index this publication - Major topics in bold
AndrostadienesAnimals
Apoptosis
Caspase 3
Cattle
Cell Hypoxia
Cell Survival
Cells, Cultured
Endothelial Cells
Enzyme Activation
Hydroxyeicosatetraenoic Acids
Lipopolysaccharides
Mice
NADPH Oxidases
Phosphatidylinositol 3-Kinases
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-akt
Pulmonary Artery
Reactive Oxygen Species