In vivo delivery of the caveolin-1 scaffolding domain inhibits nitric oxide synthesis and reduces inflammation.
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.
Bucci
M
M
Department of Pharmacology, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06536, USA.
Gratton
J P
JP
Rudic
R D
RD
Acevedo
L
L
Roviezzo
F
F
Cirino
G
G
Sessa
W C
WC
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002199:Capillary Permeability / Q000187:drug effects; D051242:Caveolin 1; D022461:Caveolins / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D014665:Vasodilator Agents / Q000037:antagonists & inhibitors*
D000893:Anti-Inflammatory Agents; C495541:Cav1 protein, mouse; D051242:Caveolin 1; D022461:Caveolins; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D014665:Vasodilator Agents; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase