Faculty Collaboration Database

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

01/13/2009

Pubmed ID

19136601

Pubmed Central ID

PMC2660237

DOI

10.1152/ajpheart.01087.2008

Scopus ID

2-s2.0-64049113217 (requires institutional sign-in at Scopus site)   45 Citations

Abstract

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 ER

Authors

Elizabeth R. Jacobs MD Emeritus Professor in the Medicine department at Medical College of Wisconsin
Meetha Medhora Professor in the Radiation Oncology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Androstadienes
Animals
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