Caveolin-1 stabilizes ATP7A, a copper transporter for extracellular SOD, in vascular tissue to maintain endothelial function

Caveolin-1 (Cav-1) is a scaffolding protein and a major component of caveolae/lipid rafts. Previous reports have shown that endothelial dysfunction in Cav-1-deficient (Cav-1 ) mice is mediated by elevated oxidative stress through endothelial nitric oxide synthase (eNOS) uncoupling and increased NADP...

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Published in:American Journal of Physiology: Cell Physiology 2020-11, Vol.319 (5), p.C933-C944
Main Authors: Sudhahar, Varadarajan, Okur, Mustafa Nazir, O'Bryan, John P, Minshall, Richard D, Fulton, David, Ushio-Fukai, Masuko, Fukai, Tohru
Format: Article
Language:English
Subjects:
Animals
Antioxidants
Aorta - cytology
Aorta - metabolism
ATP7A protein
Caveolae
Caveolin
Caveolin 1 - deficiency
Caveolin 1 - genetics
Caveolin-1
Cell surface
Copper
Copper - pharmacology
Copper Transport Proteins - genetics
Copper Transport Proteins - metabolism
Copper-Transporting ATPases - genetics
Copper-Transporting ATPases - metabolism
Endothelial cells
Endothelial Cells - cytology
Endothelial Cells - drug effects
Endothelial Cells - metabolism
Endothelium
Fibroblasts
Fibroblasts - cytology
Fibroblasts - drug effects
Fibroblasts - metabolism
Gene Expression Regulation
Gene transfer
Lipid rafts
Male
Mesenteric Arteries - cytology
Mesenteric Arteries - metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Molecular Chaperones - genetics
Molecular Chaperones - metabolism
mRNA
NAD(P)H oxidase
Nitric oxide
Nitric-oxide synthase
Oxidants
Oxidative Stress
Primary Cell Culture
Proteasome Endopeptidase Complex - metabolism
Proteasomes
Proteins
Proteolysis
Signal Transduction
Smooth muscle
Superoxide dismutase
Superoxide Dismutase - genetics
Superoxide Dismutase - metabolism
Superoxide Dismutase-1 - genetics
Superoxide Dismutase-1 - metabolism
Supplements
Transgenic mice
Ubiquitination
Ubiquitination - drug effects
Vasodilation
Vasodilation - drug effects
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Summary:Caveolin-1 (Cav-1) is a scaffolding protein and a major component of caveolae/lipid rafts. Previous reports have shown that endothelial dysfunction in Cav-1-deficient (Cav-1 ) mice is mediated by elevated oxidative stress through endothelial nitric oxide synthase (eNOS) uncoupling and increased NADPH oxidase. Oxidant stress is the net balance of oxidant generation and scavenging, and the role of Cav-1 as a regulator of antioxidant enzymes in vascular tissue is poorly understood. Extracellular SOD (SOD3) is a copper (Cu)-containing enzyme that is secreted from vascular smooth muscle cells/fibroblasts and subsequently binds to the endothelial cells surface, where it scavenges extracellular [Formula: see text] and preserves endothelial function. SOD3 activity is dependent on Cu, supplied by the Cu transporter ATP7A, but whether Cav-1 regulates the ATP7A-SOD3 axis and its role in oxidative stress-mediated vascular dysfunction has not been studied. Here we show that the activity of SOD3, but not SOD1, was significantly decreased in Cav-1 vessels, which was rescued by re-expression of Cav-1 or Cu supplementation. Loss of Cav-1 reduced ATP7A protein, but not mRNA, and this was mediated by ubiquitination of ATP7A and proteasomal degradation. ATP7A bound to Cav-1 and was colocalized with SOD3 in caveolae/lipid rafts or perinucleus in vascular tissues or cells. Impaired endothelium-dependent vasorelaxation in Cav-1 mice was rescued by gene transfer of SOD3 or by ATP7A-overexpressing transgenic mice. These data reveal an unexpected role of Cav-1 in stabilizing ATP7A protein expression by preventing its ubiquitination and proteasomal degradation, thereby increasing SOD3 activity, which in turn protects against vascular oxidative stress-mediated endothelial dysfunction.
ISSN:0363-6143
1522-1563
DOI:10.1152/ajpcell.00151.2020