Protective effects of epoxyeicosatrienoic acids on human endothelial cells from the pulmonary and coronary vasculature. Am J Physiol Heart Circ Physiol 2006 Aug;291(2):H517-31
Date
04/18/2006Pubmed ID
16617127DOI
10.1152/ajpheart.00953.2005Scopus ID
2-s2.0-33746790148 (requires institutional sign-in at Scopus site) 61 CitationsAbstract
Epoxyeicosatrienoic acids (EETs) are cytochrome P-450 (CYP) metabolites synthesized from the essential fatty acid arachidonic acid to generate four regioisomers, 14,15-, 11,12-, 8,9-, and 5,6-EET. Cultured human coronary artery endothelial cells (HCAECs) contain endogenous EETs that are increased by stimulation with physiological agonists such as bradykinin. Because EETs are known to modulate a number of vascular functions, including angiogenesis, we tested each of the four regioisomers to characterize their effects on survival and apoptosis of HCAECs and cultured human lung microvascular endothelial cells (HLMVECs). A single application of physiologically relevant concentration of 14,15-, 11,12-, and 8,9-EET but not 5,6-EET (0.75-300 nM) promoted concentration-dependent increase in cell survival of HLMVECs and HCAECs after removal of serum. The lipids also protected the same cells from death via the intrinsic, as well as extrinsic, pathways of apoptosis. EETs did not increase intracellular calcium concentration ([Ca2+]i) or phosphorylate mitogen-activated protein kinase p44/42 when applied to these cells, and their protective action was attenuated by the phosphotidylinositol-3 kinase inhibitor wortmannin (10 microM) but not the cyclooxygenase inhibitor indomethacin (20 microM). Our results demonstrate for the first time the capacity of EETs to enhance human endothelial cell survival by inhibiting both the intrinsic, as well as extrinsic, pathways of apoptosis, an important underlying mechanism that may promote angiogenesis and endothelial survival during atherosclerosis and related cardiovascular ailments.
Author List
Dhanasekaran A, Al-Saghir R, Lopez B, Zhu D, Gutterman DD, Jacobs ER, Medhora MMESH terms used to index this publication - Major topics in bold
8,11,14-Eicosatrienoic AcidAnnexin A5
Antibodies, Blocking
Apoptosis
Benzimidazoles
Blotting, Western
Calcium
Cardiotonic Agents
Caspase 3
Caspases
Cell Count
Cell Survival
Cells, Cultured
Coronary Vessels
Culture Media, Serum-Free
Endothelial Cells
Endothelium, Vascular
Fluorescent Dyes
Humans
Isomerism
Propidium
Pulmonary Circulation
Signal Transduction
Tetrazolium Salts
Thiazoles
fas Receptor
