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Therapeutic use of eNOS/Caveolin‐1 antagonistic peptides for endothelial dysfunction and atherogenesis
Author(s) -
Sharma Arpeeta,
Leung Cleo,
Stefanovic Nada,
Haan Judy,
Bernatchez Pascal
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.672.4
Subject(s) - enos , nitric oxide , caveolin 1 , in vivo , endothelial dysfunction , knockout mouse , oxidative stress , pharmacology , endothelium , nitric oxide synthase type iii , nitric oxide synthase , endocrinology , chemistry , medicine , biology , receptor , microbiology and biotechnology
Rationale Endothelial dysfunction, which is characterized by a reduction in nitric oxide (NO) bioavailability, is an early pro‐atherogenic step. Endothelial nitric oxide synthase (eNOS), the enzyme responsible for the constitutive production of NO, is negatively regulated by its association to Caveolin‐1 (Cav‐1), the major coat protein of caveolae . Whether antagonizing the eNOS/Cav‐1 interaction is an anti‐atherosclerotic drug target is unknown. Objective We have recently shown that a mutant Cav‐1 derived peptide (CavNoxin) can increase NO release by antagonizing eNOS binding to Cav‐1 (Bernatchez, Sharma et al., JCI 2011). Since upregulating NO production is therapeutically relevant in atherosclerosis we hypothesized that CavNoxin can attenuate atherosclerotic progression in vivo . Methods & Results ApoE knockout mice were placed on a high fat diet for 12 weeks and were injected with either CavNoxin (2.5mg/kg) or vehicle peptide every 3 days. At the end of the 12 weeks, atherosclerotic lesions were analysed. CavNoxin treatment attenuated atherosclerotic lesions in the aorta and aortic sinuses by 42% and 21% respectively, as compared to vehicle controls. In addition, Cavnoxin reduced VCAM‐1 (adhesion molecule) expression and oxidative stress (measured by DHE and nitrotyrosine staining) in vivo. Conclusion These data are the first to show an effect of the eNOS/Cav‐1 antagonism in atherosclerosis.