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1 Div Pulmonary and Critical Care, Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
2 Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
3 Div Cardiovascular Medicine, Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
* To whom correspondence should be addressed. E-mail: medhoram{at}mcw.edu.
Epoxyeicosatrienoic acids (EETs) are cytochrome P450 (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 which are increased by stimulation with physiological agonists such as bradykinin. Since 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 [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 µM), but not the cyclooxygenase inhibitor indomethacin (20 µM). 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.
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