This Article Full Text Full Text (PDF) Data Supplement Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fisslthaler, B. Articles by Busse, R. Search for Related Content PubMed PubMed Citation Articles by Fisslthaler, B. Articles by Busse, R. Related Collections Cell signalling/signal transduction Physiological and pathological control of gene expression Coronary circulation Other Vascular biology

(Hypertension. 2001;38:1427.)
© 2001 American Heart Association, Inc.

Fourth Workshop on Structure and Function of Large Arteries: Part III

Cyclic Stretch Enhances the Expression and Activity of Coronary Endothelium-Derived Hyperpolarizing Factor Synthase

Beate Fisslthaler; Rüdiger Popp; U. Ruth Michaelis; Ladislau Kiss; Ingrid Fleming; Rudi Busse

From the Institut für Kardiovaskuläre Physiologie, Klinikum der J.W.G.-Universität (B.F., R.P., U.R.M., I.F., R.B.), Frankfurt am Main, Germany; and Zentrum der Inneren Medizin, Justus Liebig Universität Gießen (L.K.), Gießen, Germany.

Correspondence to Dr Ingrid Fleming, Institut für Kardiovaskuläre Physiologie, Klinikum der J.W.G.-Universität, Theodor-Stern-Kai 7, D-60590 Frankfurt am Main, Germany. E-mail fleming{at}em.uni-frankfurt.de

Abstract

Endothelium-derived hyperpolarizing factor (EDHF) mediates NO/prostacyclin-independent relaxation in the coronary circulation. Because hemodynamic stimuli modulate endothelial gene expression and because coronary arteries are subjected to pronounced variations in vessel distension, we determined the effects of cyclic stretch on the expression and activity of the coronary EDHF synthase/cytochrome P450 (CYP) 2C8/9. In cultured porcine coronary and human umbilical vein endothelial cells, acute application of cyclic stretch (6%, 1 Hz, 10 minutes) elicited the generation of 8,9-epoxyeicosatrienoic acid (EET), 11,12-EET, and 14,15-EET. Prolonged stretch (4 to 36 hours) increased the expression of CYP 2C mRNA and protein 5- to 10-fold and was accompanied by a 4- to 8-fold increase in EET generation. A corresponding increase in CYP 2C mRNA and protein was also observed in pressurized segments of porcine coronary artery perfused under pulsatile conditions (8%, 1 Hz) for 6 hours. Although in cultured endothelial cells, cyclic stretch elicited the rapid activation of tyrosine kinases as well as Akt and the p38 mitogen-activated protein kinase, the mechanism by which cyclic stretch induces the expression of CYP 2C could not be elucidated, because inhibitors of these pathways induced CYP 2C expression in cells maintained under static conditions. These results have identified coronary EDHF synthase/CYP 2C as a novel mechanosensitive gene product in native and cultured endothelial cells. Because this enzyme generates both EETs and superoxide anions, this finding has wide-reaching implications for vascular homeostasis in conditions of manifest endothelial dysfunction.

Key Words: endothelium-derived factor • cytochrome P450 • arteries • inositol • protein kinases

This article has been cited by other articles:

				Y. Chawengsub, K. M. Gauthier, K. Nithipatikom, B. D. Hammock, J. R. Falck, D. Narsimhaswamy, and W. B. Campbell Identification of 13-Hydroxy-14,15-epoxyeicosatrienoic Acid as an Acid-stable Endothelium-derived Hyperpolarizing Factor in Rabbit Arteries J. Biol. Chem., November 6, 2009; 284(45): 31280 - 31290. [Abstract] [Full Text] [PDF]

				F. Krotz, N. Hellwig, M. A. Burkle, S. Lehrer, T. Riexinger, H. Mannell, H.-Y. Sohn, V. Klauss, and U. Pohl A sulfaphenazole-sensitive EDHF opposes platelet-endothelium interactions in vitro and in the hamster microcirculation in vivo Cardiovasc Res, October 4, 2009; (2009) cvp301v2. [Abstract] [Full Text] [PDF]

				T. Pearson, A. Y. Warren, D. A. Barrett, and R. N. Khan Detection of EETs and HETE-generating cytochrome P-450 enzymes and the effects of their metabolites on myometrial and vascular function Am J Physiol Endocrinol Metab, September 1, 2009; 297(3): E647 - E656. [Abstract] [Full Text] [PDF]

				A. E. Loot, R. Popp, B. Fisslthaler, J. Vriens, B. Nilius, and I. Fleming Role of cytochrome P450-dependent transient receptor potential V4 activation in flow-induced vasodilatation Cardiovasc Res, December 1, 2008; 80(3): 445 - 452. [Abstract] [Full Text] [PDF]

				A. C. Webler, U. R. Michaelis, R. Popp, E. Barbosa-Sicard, A. Murugan, J. R. Falck, B. Fisslthaler, and I. Fleming Epoxyeicosatrienoic acids are part of the VEGF-activated signaling cascade leading to angiogenesis Am J Physiol Cell Physiol, November 1, 2008; 295(5): C1292 - C1301. [Abstract] [Full Text] [PDF]

				W. Yang, V. R. Tuniki, S. Anjaiah, J. R. Falck, C. J. Hillard, and W. B. Campbell Characterization of Epoxyeicosatrienoic Acid Binding Site in U937 Membranes Using a Novel Radiolabeled Agonist, 20-125I-14,15-Epoxyeicosa-8(Z)-Enoic Acid J. Pharmacol. Exp. Ther., March 1, 2008; 324(3): 1019 - 1027. [Abstract] [Full Text] [PDF]

				N. Westerhof, C. Boer, R. R. Lamberts, and P. Sipkema Cross-talk between cardiac muscle and coronary vasculature. Physiol Rev, October 1, 2006; 86(4): 1263 - 1308. [Abstract] [Full Text] [PDF]

				U. R. Michaelis, J. R. Falck, R. Schmidt, R. Busse, and I. Fleming Cytochrome P4502C9-Derived Epoxyeicosatrienoic Acids Induce the Expression of Cyclooxygenase-2 in Endothelial Cells Arterioscler Thromb Vasc Biol, February 1, 2005; 25(2): 321 - 326. [Abstract] [Full Text] [PDF]

				S. Kippenberger, S. Loitsch, M. Guschel, J. Muller, Y. Knies, R. Kaufmann, and A. Bernd Mechanical Stretch Stimulates Protein Kinase B/Akt Phosphorylation in Epidermal Cells via Angiotensin II Type 1 Receptor and Epidermal Growth Factor Receptor J. Biol. Chem., January 28, 2005; 280(4): 3060 - 3067. [Abstract] [Full Text] [PDF]

				W. Zheng, L. P. Christensen, and R. J. Tomanek Stretch induces upregulation of key tyrosine kinase receptors in microvascular endothelial cells Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2739 - H2745. [Abstract] [Full Text] [PDF]

				F. Krotz, T. Riexinger, M. A. Buerkle, K. Nithipatikom, T. Gloe, H.-Y. Sohn, W. B. Campbell, and U. Pohl Membrane Potential-Dependent Inhibition of Platelet Adhesion to Endothelial Cells by Epoxyeicosatrienoic Acids Arterioscler Thromb Vasc Biol, March 1, 2004; 24(3): 595 - 600. [Abstract] [Full Text]

				K. M. Gauthier, N. Spitzbarth, E. M. Edwards, and W. B. Campbell Apamin-Sensitive K+ Currents Mediate Arachidonic Acid-Induced Relaxations of Rabbit Aorta Hypertension, February 1, 2004; 43(2): 413 - 419. [Abstract] [Full Text] [PDF]

				S. Earley, A. Pastuszyn, and B. R. Walker Cytochrome P-450 epoxygenase products contribute to attenuated vasoconstriction after chronic hypoxia Am J Physiol Heart Circ Physiol, June 5, 2003; 285(1): H127 - H136. [Abstract] [Full Text] [PDF]

				S. Gschwend, H. Buikema, R. H. Henning, Y. M. Pinto, D. de Zeeuw, and W. H. van Gilst Endothelial dysfunction and infarct-size relate to impaired EDHF response in rat experimental chronic heart failure Eur J Heart Fail, March 1, 2003; 5(2): 147 - 154. [Abstract] [Full Text] [PDF]

				X. Peng, S. Haldar, S. Deshpande, K. Irani, and D. A. Kass Wall Stiffness Suppresses Akt/eNOS and Cytoprotection in Pulse-Perfused Endothelium Hypertension, February 1, 2003; 41(2): 378 - 381. [Abstract] [Full Text] [PDF]

				T. Hillig, P. Krustrup, I. Fleming, T. Osada, B. Saltin, and Y. Hellsten Cytochrome P450 2C9 plays an important role in the regulation of exercise-induced skeletal muscle blood flow and oxygen uptake in humans J. Physiol., January 1, 2003; 546(1): 307 - 314. [Abstract] [Full Text] [PDF]

				P. R. Standley, A. Camaratta, B. P. Nolan, C. T. Purgason, and M. A. Stanley Cyclic stretch induces vascular smooth muscle cell alignment via NO signaling Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1907 - H1914. [Abstract] [Full Text] [PDF]

				J. W. Newman, T. Watanabe, and B. D. Hammock The simultaneous quantification of cytochrome P450 dependent linoleate and arachidonate metabolites in urine by HPLC-MS/MS J. Lipid Res., September 1, 2002; 43(9): 1563 - 1578. [Abstract] [Full Text] [PDF]

				J. Bauersachs, M. Christ, G. Ertl, U.R. Michaelis, B. Fisslthaler, R. Busse, and I. Fleming Cytochrome P450 2C expression and EDHF-mediated relaxation in porcine coronary arteries is increased by cortisol Cardiovasc Res, June 1, 2002; 54(3): 669 - 675. [Abstract] [Full Text] [PDF]

				K. M. Gauthier, C. Deeter, U. M. Krishna, Y. K. Reddy, M. Bondlela, J.R. Falck, and W. B. Campbell 14,15-Epoxyeicosa-5(Z)-enoic Acid: A Selective Epoxyeicosatrienoic Acid Antagonist That Inhibits Endothelium-Dependent Hyperpolarization and Relaxation in Coronary Arteries Circ. Res., May 17, 2002; 90(9): 1028 - 1036. [Abstract] [Full Text] [PDF]

				M. Potente, U. R. Michaelis, B. Fisslthaler, R. Busse, and I. Fleming Cytochrome P450 2C9-induced Endothelial Cell Proliferation Involves Induction of Mitogen-activated Protein (MAP) Kinase Phosphatase-1, Inhibition of the c-Jun N-terminal Kinase, and Up-regulation of Cyclin D1 J. Biol. Chem., May 3, 2002; 277(18): 15671 - 15676. [Abstract] [Full Text] [PDF]