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(Circulation Research. 2002;90:838.)
© 2002 American Heart Association, Inc.

Editorials

Heat Shock Protein 90 in Endothelial Nitric Oxide Synthase Signaling

Following the Lead(er)?

J.-L. Balligand

From the Unit of Pharmacology and Therapeutics, Department of Medicine, University of Louvain Medical School, Brussels, Belgium.

Correspondence to J.-L. Balligand, Unit of Pharmacology and Therapeutics, FATH 5349, Department of Medicine, University of Louvain Medical School, 53, Ave E Mounier, 1200 Brussels, Belgium. E-mail Balligand@ mint.ucl.ac.be

Key Words: nitric oxide • caveolin • heat shock protein 90 • endothelium

Endothelial nitric oxide synthase (eNOS) produces NO (and/or other reactive nitrogen species) in vascular endothelial cells and cardiomyocytes in response to a variety of agonists and mechanical stimuli (eg, stretch, shear). The central role of NO in the homeostatic balance of the healthy endothelium justifies a growing interest in the molecular mechanisms governing its production by eNOS in a stimulus- and (sub)cellular-specific fashion, including in response to a variety of drugs (eg, statins, angiotensin-converting enzyme inhibitors, ß-blockers) widely used for the treatment of cardiovascular diseases. In addition to transcriptional regulation, eNOS activity is regulated posttranslationally by the availability of its substrate, L-arginine, and cofactors (eg, tetrahydrobiopterin [BH₄]), as well as protein-protein interactions with a number of partners that activate or inhibit the enzyme. Because new information on transient clustering of signaling molecules is likely to accumulate, especially with the use of functional proteomics,¹ thereby potentially increasing the list of eNOS regulators, one may legitimately ask these fundamental questions: (1) how do these different proteins associate with each other in a discrete subcellular compartment and in what sequential order and (2) how important is their (often transient) association for the proper functioning of any signaling pathway, especially in intact cells or in vivo. The availability of convergent data on x-ray crystal structure of the eNOS oxygenase domain, together with results using site-directed mutagenesis (or gene deletion experiments, eg, for caveolin-1 and caveolin-3) on several of the putative eNOS partners, now provides at least some of the answers and motivates . . . [Full Text of this Article]

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