Abstract
Caveolin-1, the primary coat protein of caveolae, has been implicated as a regulator of signal transduction through binding of its “scaffolding domain” to key signaling molecules. However, the physiological importance of caveolin-1 in regulating signaling has been difficult to distinguish from its traditional functions in caveolae assembly, transcytosis, and cholesterol transport. To directly address the importance of the caveolin scaffolding domain in vivo, we generated a chimeric peptide with a cellular internalization sequence fused to the caveolin-1 scaffolding domain (amino acids 82–101). The chimeric peptide was efficiently taken up into blood vessels and endothelial cells, resulting in selective inhibition of acetylcholine (Ach)-induced vasodilation and nitric oxide (NO) production, respectively. More importantly, systemic administration of the peptide to mice suppressed acute inflammation and vascular leak to the same extent as a glucocorticoid or an endothelial nitric oxide synthase (eNOS) inhibitor. These data imply that the caveolin-1 scaffolding domain can selectively regulate signal transduction to eNOS in endothelial cells and that small-molecule mimicry of this domain may provide a new therapeutic approach.
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Acknowledgements
The authors wish to thank J.K. Crawford and I. Laroche from the W.M. Keck biotechnology resource center at Yale University School of Medicine. This work is supported by grants from the National Institute of Health (HL57665, HL 61371 and HL 64793 to W.C.S., a grant-in-aid from the American Heart Association (National Grant to W.C.S.). W.C.S. is an established investigator of the American Heart Association. J-P.G. is supported in part by fellowships from the Heart and Stroke Foundation of Canada, Fonds pour la Formation de Chercheurs etl' Aida a la Recherche (FCAR), and from the Canadian Institutes of Health Research.
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Bucci, M., Gratton, JP., Rudic, R. et al. In vivo delivery of the caveolin-1 scaffolding domain inhibits nitric oxide synthesis and reduces inflammation. Nat Med 6, 1362–1367 (2000). https://doi.org/10.1038/82176
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DOI: https://doi.org/10.1038/82176
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