HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 47, 48794-48800, November 19, 2004

This Article Full Text Full Text (PDF) All Versions of this Article: 279/47/48794    most recent M313897200v1 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lungu, A. O. Articles by Berk, B. C. Search for Related Content PubMed PubMed Citation Articles by Lungu, A. O. Articles by Berk, B. C. Social Bookmarking                      What's this?

Cyclosporin A Inhibits Flow-mediated Activation of Endothelial Nitric-oxide Synthase by Altering Cholesterol Content in Caveolae^*

Andreea O. Lungu, Zheng-Gen Jin, Hideyuki Yamawaki, Tatsuo Tanimoto, Chelsea Wong, and Bradford C. Berk

From the Department of Medicine and Center for Cardiovascular Research, University of Rochester School of Medicine and Dentistry, Aab Institute of Biomedical Sciences, Rochester, New York 14642

Fluid shear stress generated by blood flowing over the endothelium is a major determinant of arterial tone, vascular remodeling, and atherogenesis. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays an essential role in regulation of vascular function and structure by blood flow. Although cyclosporin A (CsA), an inhibitory ligand of cyclophilin A, is a widely used immunosuppressive drug, it causes arterial hypertension in part by impairing eNOS-dependent vasodilation. Here we show that CsA inhibits fluid shear stress-mediated eNOS activation in endothelial cells via decreasing cholesterol content in caveolae. Exposure of cultured bovine aortic endothelial cells to 1 µM CsA for 1 h significantly inhibited NO production and eNOS phosphorylation at Ser-1179 induced by flow (shear stress = 12 dynes/cm²). The effect of CsA was not related to inhibition of two known eNOS kinases, protein kinase B (Akt) and protein kinase A, because CsA did not affect Akt or protein kinase A activation. In rabbit aorta perfused ex vivo, CsA also significantly inhibited flow-induced eNOS phosphorylation at Ser-1179 but had no effect on Akt measured by phosphorylation at Ser-473. However, CsA treatment decreased cholesterol content in caveolae and displaced eNOS from caveolae, which may be caused by CsA disrupting the association of caveolin-1 and cyclophilin A. The magnitude of the cholesterol depleting effect was similar to that of -cyclodextrin, a cholesterol-binding molecule, and -cyclodextrin had a similar inhibitory effect on flow-mediated eNOS activation. Treating bovine aortic endothelial cells for 24 h with 30 µg/ml cholesterol blocked the CsA effect and restored eNOS phosphorylation in response to flow. These data suggest that decreasing cholesterol content in caveolae by CsA is a potentially important pathogenic mechanism for CsA-induced endothelial dysfunction and hypertension.

Received for publication, December 19, 2003 , and in revised form, July 26, 2004.

^* This work was supported by American Heart Association Grant 0235480T (to Z.-G. J.) and National Institutes of Health Grant HL-64839 (to B. C. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These authors contributed equally to this work.

To whom correspondence should be addressed: University of Rochester, Center for Cardiovascular Research, 601 Elmwood Ave., Box 679, Rochester, NY 14642. Tel.: 585-273-1946; Fax: 585-273-1497; E-mail: zheng-gen_jin{at}urmc.rochester.edu.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				X. Xu, B. Sook Jhun, C. Hoon Ha, and Z.-G. Jin Molecular Mechanisms of Ghrelin-Mediated Endothelial Nitric Oxide Synthase Activation Endocrinology, August 1, 2008; 149(8): 4183 - 4192. [Abstract] [Full Text] [PDF]

				D. Ramzy, L. C. Tumiati, E. Tepperman, R. Sheshgiri, J. Jackman, M. Badiwala, and V. Rao Dual immunosuppression enhances vasomotor injury: Interactive effect between endothelin-1 and nitric oxide bioavailability. J. Thorac. Cardiovasc. Surg., April 1, 2008; 135(4): 938 - 944. [Abstract] [Full Text] [PDF]

				C. H. Ha, A. M. Bennett, and Z.-G. Jin A Novel Role of Vascular Endothelial Cadherin in Modulating c-Src Activation and Downstream Signaling of Vascular Endothelial Growth Factor J. Biol. Chem., March 14, 2008; 283(11): 7261 - 7270. [Abstract] [Full Text] [PDF]

				E. Raichlin, J.-H. Bae, Z. Khalpey, B. S. Edwards, W. K. Kremers, A. L. Clavell, R. J. Rodeheffer, R. P. Frantz, C. Rihal, A. Lerman, et al. Conversion to Sirolimus as Primary Immunosuppression Attenuates the Progression of Allograft Vasculopathy After Cardiac Transplantation Circulation, December 4, 2007; 116(23): 2726 - 2733. [Abstract] [Full Text] [PDF]

				K. Yamamoto, N. Shimizu, S. Obi, S. Kumagaya, Y. Taketani, A. Kamiya, and J. Ando Involvement of cell surface ATP synthase in flow-induced ATP release by vascular endothelial cells Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1646 - H1653. [Abstract] [Full Text] [PDF]

				T. Nakagawa Uncoupling of the VEGF-endothelial nitric oxide axis in diabetic nephropathy: an explanation for the paradoxical effects of VEGF in renal disease Am J Physiol Renal Physiol, June 1, 2007; 292(6): F1665 - F1672. [Abstract] [Full Text] [PDF]

				F. A. Sanchez, N. B. Savalia, R. G. Duran, B. K. Lal, M. P. Boric, and W. N. Duran Functional significance of differential eNOS translocation Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1058 - H1064. [Abstract] [Full Text] [PDF]

				S. Di Paolo, A. Teutonico, D. Leogrande, C. Capobianco, and P. F. Schena Chronic Inhibition of Mammalian Target of Rapamycin Signaling Downregulates Insulin Receptor Substrates 1 and 2 and AKT Activation: A Crossroad between Cancer and Diabetes? J. Am. Soc. Nephrol., August 1, 2006; 17(8): 2236 - 2244. [Abstract] [Full Text] [PDF]

				R. Komers, W. E. Schutzer, J. F. Reed, J. N. Lindsley, T. T. Oyama, D. C. Buck, S. L. Mader, and S. Anderson Altered Endothelial Nitric Oxide Synthase Targeting and Conformation and Caveolin-1 Expression in the Diabetic Kidney Diabetes, June 1, 2006; 55(6): 1651 - 1659. [Abstract] [Full Text] [PDF]

				Y. Zhang, T.-S. Lee, E. M. Kolb, K. Sun, X. Lu, F. M. Sladek, G. S. Kassab, T. Garland Jr, and J. Y.-J. Shyy AMP-Activated Protein Kinase Is Involved in Endothelial NO Synthase Activation in Response to Shear Stress Arterioscler. Thromb. Vasc. Biol., June 1, 2006; 26(6): 1281 - 1287. [Abstract] [Full Text] [PDF]

				Z.-G. Jin Where is endothelial nitric oxide synthase more critical: plasma membrane or Golgi? Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 959 - 961. [Full Text] [PDF]

				J. M. Cale and I. M. Bird Dissociation of endothelial nitric oxide synthase phosphorylation and activity in uterine artery endothelial cells Am J Physiol Heart Circ Physiol, April 1, 2006; 290(4): H1433 - H1445. [Abstract] [Full Text] [PDF]

				C. Wong and Z.-G. Jin Protein Kinase C-dependent Protein Kinase D Activation Modulates ERK Signal Pathway and Endothelial Cell Proliferation by Vascular Endothelial Growth Factor J. Biol. Chem., September 30, 2005; 280(39): 33262 - 33269. [Abstract] [Full Text] [PDF]