title: Direct Endothelial Nitric Oxide Synthase Activation Provides Atheroprotection in Diabetes-Accelerated Atherosclerosis.
abstract: Patients with diabetes have an increased risk of developing atherosclerosis. Endothelial dysfunction, characterized by the lowered bioavailability of endothelial NO synthase (eNOS)-derived NO, is a critical inducer of atherosclerosis. However, the protective aspect of eNOS in diabetes-associated atherosclerosis remains controversial, a likely consequence of its capacity to release both protective NO or deleterious oxygen radicals in normal and disease settings, respectively. Harnessing the atheroprotective activity of eNOS in diabetic settings remains elusive, in part due to the lack of endogenous eNOS-specific NO release activators. We have recently shown in vitro that eNOS-derived NO release can be increased by blocking its binding to Caveolin-1, the main coat protein of caveolae, using a highly specific peptide, CavNOxin. However, whether targeting eNOS using this peptide can attenuate diabetes-associated atherosclerosis is unknown. In this study, we show that CavNOxin can attenuate atherosclerotic burden by ∼84% in vivo. In contrast, mice lacking eNOS show resistance to CavNOxin treatment, indicating eNOS specificity. Mechanistically, CavNOxin lowered oxidative stress markers, inhibited the expression of proatherogenic mediators, and blocked leukocyte-endothelial interactions. These data are the first to show that endogenous eNOS activation can provide atheroprotection in diabetes and suggest that CavNOxin is a viable strategy for the development of antiatherosclerotic compounds.
authors.affiliation: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada Baker IDI Heart and Diabetes Institute, Diabetic Complications Division, Melbourne, Victoria, Australia.
authors.forename: Arpeeta
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Sellers
authors.affiliation: Baker IDI Heart and Diabetes Institute, Diabetic Complications Division, Melbourne, Victoria, Australia.
authors.forename: Nada
authors.initials: N
authors.lastname: Stefanovic
authors.affiliation: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Cleo
authors.initials: C
authors.lastname: Leung
authors.affiliation: Baker IDI Heart and Diabetes Institute, Diabetic Complications Division, Melbourne, Victoria, Australia.
authors.forename: Sih Min
authors.initials: SM
authors.lastname: Tan
authors.affiliation: Baker IDI Heart and Diabetes Institute, Diabetic Complications Division, Melbourne, Victoria, Australia.
authors.forename: Olivier
authors.initials: O
authors.lastname: Huet
authors.affiliation: Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: David J
authors.initials: DJ
authors.lastname: Granville
authors.affiliation: Baker IDI Heart and Diabetes Institute, Diabetic Complications Division, Melbourne, Victoria, Australia Department of Immunology, Monash University, Melbourne, Victoria, Australia.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.affiliation: Baker IDI Heart and Diabetes Institute, Diabetic Complications Division, Melbourne, Victoria, Australia Department of Immunology, Monash University, Melbourne, Victoria, Australia judy.dehaan@bakeridi.edu.au pascal.bernatchez@ubc.ca.
authors.forename: Judy B
authors.initials: JB
authors.lastname: de Haan
authors.affiliation: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada Centre for Heart Lung Innovation, St. Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada judy.dehaan@bakeridi.edu.au pascal.bernatchez@ubc.ca.
authors.forename: Pascal
authors.initials: P
authors.lastname: Bernatchez
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism*; D021941:Caveolae / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D003925:Diabetic Angiopathies / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
chemical_list: D051242:Caveolin 1; D052250:Nitric Oxide Synthase Type III