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Am J Physiol Heart Circ Physiol 291: H517-H531, 2006. First published April 14, 2006; doi:10.1152/ajpheart.00953.2005
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Regulation of Cardiovascular Functions by Eicosanoids and other Lipid Mediators

Protective effects of epoxyeicosatrienoic acids on human endothelial cells from the pulmonary and coronary vasculature

Anuradha Dhanasekaran,1,4 Rula Al-Saghir,1,4 Bernardo Lopez,2 Daling Zhu,1,4 David D. Gutterman,3,4 Elizabeth R. Jacobs,1,2 and Meetha Medhora1,4

1Division of Pulmonary and Critical Care, Department of Medicine; 2Department of Physiology; 3Division of Cardiology, Department of Medicine and Zablocki Veterans Affairs Medical Center; and 4Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin

Submitted 6 September 2005 ; accepted in final form 3 March 2006

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 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.

cytochrome P-450; eicosanoids; epoxygenase; apoptosis; calcium signaling


Address for reprint requests and other correspondence: M. Medhora, Cardiovascular Center MEB M4870, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226 (e-mail: medhoram{at}mcw.edu)




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