Circulation Research. 2001;89:866-873
Published online before print October 18, 2001, doi: 10.1161/hh2201.100319
Published online before print October 18, 2001, doi: 10.1161/hh2201.100319
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© 2001 American Heart Association, Inc.
Molecular Medicine |
Hsp90 and Caveolin Are Key Targets for the Proangiogenic Nitric Oxide–Mediated Effects of Statins
From the Department of Medicine, University of Louvain Medical School, Brussels, Belgium.
Correspondence to Dr Olivier Feron or Dr Jean-Luc Balligand, University of Louvain Medical School Pharmacology and Therapeutics Unit, UCL-FATH 5349, 53 Ave E. Mounier, B-1200 Brussels, Belgium. E-mail feron{at}mint.ucl.ac.be or balligand@mint.ucl.ac.be
Abstract—— 3-Hydroxy-3-methylglutaryl (HMG)–coenzyme A reductase inhibitors or statins exert direct beneficial effects on the endothelium in part through an increase in nitric oxide (NO) production. Here, we examined whether posttranslational modifications of the endothelial NO synthase (eNOS) could account for the proangiogenic effects of statins. We used endothelial cells (ECs) isolated from cardiac microvasculature, aorta, and umbilical veins, as well as dissected microvessels and aortic rings, that were cultured on reconstituted basement membrane matrix (Matrigel). Tube or precapillary formation was evaluated after statin treatment, in parallel with immunoblotting and immunoprecipitation experiments. Atorvastatin stimulated NO-dependent angiogenesis from both isolated and outgrowing (vessel-derived) ECs, independently of changes in eNOS expression. We found that in macro- but not microvascular ECs, atorvastatin stabilized tube formation through a decrease in caveolin abundance and its inhibitory interaction with eNOS. We also identified the chaperone protein hsp90 as a key target for the proangiogenic effects of statins. Using geldanamycin, an inhibitor of hsp90 function, and overexpression of recombinant hsp90, we documented that the statin-induced phosphorylation of eNOS on Ser1177 was directly dependent on the ability of hsp90 to recruit Akt in the eNOS complex. Finally, we showed that statin promoted the tyrosine phosphorylation of hsp90 and the direct interaction of hsp90 with Akt, which further potentiated the NO-dependent angiogenic processes. Our study provides new mechanistic insights into the NO-mediated angiogenic effects of statins and underscores the potential of these drugs and other modulators of hsp90 and caveolin abundance to promote neovascularization in disease states associated or not with atherosclerosis.
Key Words: statin • angiogenesis • nitric oxide • hsp90 • caveolin
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|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
M. Pelat, C. Dessy, P. Massion, J.-P. Desager, O. Feron, and J.-L. Balligand Rosuvastatin Decreases Caveolin-1 and Improves Nitric Oxide-Dependent Heart Rate and Blood Pressure Variability in Apolipoprotein E-/- Mice In Vivo Circulation, May 20, 2003; 107(19): 2480 - 2486. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Sonveaux, A. Brouet, X. Havaux, V. Gregoire, C. Dessy, J.-L. Balligand, and O. Feron Irradiation-induced Angiogenesis through the Up-Regulation of the Nitric Oxide Pathway: Implications for Tumor Radiotherapy Cancer Res., March 1, 2003; 63(5): 1012 - 1019. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. M. Bell and D. M. Yellon Atorvastatin, administered at the onset of reperfusion, and independent oflipid lowering, protects the myocardiumby up-regulating a pro-survival pathway J. Am. Coll. Cardiol., February 5, 2003; 41(3): 508 - 515. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P.O Bonetti, L.O Lerman, C Napoli, and A Lerman Statin effects beyond lipid lowering--are they clinically relevant? Eur. Heart J., February 1, 2003; 24(3): 225 - 248. [Full Text] [PDF]
|
|
|
|
|
|
G. P. van Nieuw Amerongen, P. Koolwijk, A. Versteilen, and V. W.M. van Hinsbergh Involvement of RhoA/Rho Kinase Signaling in VEGF-Induced Endothelial Cell Migration and Angiogenesis In Vitro Arterioscler. Thromb. Vasc. Biol., February 1, 2003; 23(2): 211 - 217. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. S. Bredt Nitric oxide signaling specificity -- the heart of the problem J. Cell Sci., January 1, 2003; 116(1): 9 - 15. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Skaletz-Rorowski, M. Lutchman, Y. Kureishi, D. J. Lefer, J. R. Faust, and K. Walsh HMG-CoA reductase inhibitors promote cholesterol-dependent Akt/PKB translocation to membrane domains in endothelial cells Cardiovasc Res, January 1, 2003; 57(1): 253 - 264. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. L. Burnett Nitric Oxide Regulation of Penile Erection: Biology and Therapeutic Implications J Androl, September 1, 2002; 23(5): S20 - S26. [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Goligorsky, H. Li, S. Brodsky, and J. Chen Relationships between caveolae and eNOS: everything in proximity and the proximity of everything Am J Physiol Renal Physiol, July 1, 2002; 283(1): F1 - F10. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Shiojima and K. Walsh Role of Akt Signaling in Vascular Homeostasis and Angiogenesis Circ. Res., June 28, 2002; 90(12): 1243 - 1250. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-L. Balligand Heat Shock Protein 90 in Endothelial Nitric Oxide Synthase Signaling: Following the Lead(er)? Circ. Res., May 3, 2002; 90(8): 838 - 841. [Full Text] [PDF]
|
|
|
|
|
|
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|
|
|
|
|
|
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