Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 121, Issue 9, Pages 3747-3755Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI44778
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Funding
- NIH [R01 HL64793, R01 HL61371, R01 HL081190, HL096670, P01 HL70295]
- Canadian Institutes for Health Research (CIHR)
- Michael Smith Foundation for Health Research (MSFHR)
- Canadian Foundation for Innovation
- British Columbia Knowledge Development Fund
- National Kidney Foundation
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Aberrant regulation of eNOS and associated NO release are directly linked with various vascular diseases. Caveolin-1 (Cav-1), the main coat protein of caveolae, is highly expressed in endothelial cells. Its scaffolding domain serves as an endogenous negative regulator of eNOS function. Structure-function analysis of Cav-1 has shown that phenylalanine 92 (F92) is critical for the inhibitory actions of Cav-1 toward eNOS. Herein, we show that F92A-Cav-1 and a mutant cell-permeable scaffolding domain peptide called Cavnoxin can increase basal NO release in eNOS-expressing cells. Cavnoxin reduced vascular tone ex vivo and lowered blood pressure in normal mice. In contrast, similar experiments performed with eNOS- or Cav-1-deficient mice showed that the vasodilatory effect of Cavnoxin is abolished in the absence of these gene products, which indicates a high level of eNOS/Cav-1 specificity. Mechanistically, biochemical assays indicated that noninhibitory F92A-Cav-1 and Cavnoxin specifically disrupted the inhibitory actions of endogenous Cav-1 toward eNOS and thereby enhanced basal NO release. Collectively, these data raise the possibility of studying the inhibitory influence of Cav-1 on eNOS without interfering with the other actions of endogenous Cav-1. They also suggest a therapeutic application for regulating the eNOS/Cav-1 interaction in diseases characterized by decreased NO release.
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