Dynamic activation of endothelial nitric oxide synthase by Hsp90

• Published in: Nature (London) Vol. 392; no. 6678; pp. 821 - 824
• Main Authors: Sessa, William C, García-Cardeña, Guillermo, Fan, Roger, Shah, Vijay, Sorrentino, Raffaella, Cirino, Giuseppe, Papapetropoulos, Andreas
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 23-04-1998; Nature Publishing Group
• Subjects: Analytical, structural and metabolic biochemistry; Animals; Antibiotics, Antineoplastic - pharmacology; Aorta; Benzoquinones; Biological and medical sciences; Blood vessels; Cattle; Cell Line; Cell physiology; Cellular biology; COS Cells; Endothelial Growth Factors - metabolism; Endothelium, Vascular - enzymology; Enzyme Activation; Enzymes and enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Histamine - metabolism; HSP90 Heat-Shock Proteins - antagonists & inhibitors; HSP90 Heat-Shock Proteins - metabolism; Humans; Lactams, Macrocyclic; Lymphokines - metabolism; Molecular and cellular biology; Muscle Relaxation - drug effects; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase - metabolism; Oxidoreductases; Precipitin Tests; Proteins; Quinones - pharmacology; Rats; Shear stress; Signal Transduction; Space life sciences; Stress, Mechanical; Transfection; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Human; Signal transduction; Endothelial cell; Enzyme; Nitric oxide; Heat shock protein; Oxidoreductases; In vitro; Umbilical vein; Nitric-oxide synthase
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/33934

Heat-shock protein 90 (Hsp90) coordinates the trafficking and regulation of diverse signalling proteins, but its precise role in regulating specific cellular targets is not known,. Here we show that Hsp90 associates with endothelial nitric oxide synthase (eNOS) and is rapidly recruited to the eNOS complex by agonists that stimulate production of nitric oxide, namely vascular endothelial growth factor, histamine and fluid shear stress. Moreover, the binding of Hsp90 to eNOS enhances the activation of eNOS. Inhibition of signalling through Hsp90 attenuates both agonist-stimulated production of nitric oxide and endothelium-dependent relaxation of isolated blood vessels. Our results indicate that Hsp90 facilitates signalling mediated by growth-factor, G-protein and mechanotransduction pathways that lead to the activation of eNOS. These observations indicate that in addition to its role as a molecular chaperone involved in protein folding and maturation, Hsp90 may also be recruited to cellular targets depending on the activation state of the cell.