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Monosialoganglioside-Containing Nanoliposomes Restore Endothelial Function Impaired by AL Amyloidosis Light Chain Proteins.
- Source :
-
Journal of the American Heart Association [J Am Heart Assoc] 2016 Jun 13; Vol. 5 (6). Date of Electronic Publication: 2016 Jun 13. - Publication Year :
- 2016
-
Abstract
- Background: Light chain amyloidosis (AL) is associated with high mortality, especially in patients with advanced cardiovascular involvement. It is caused by toxicity of misfolded light chain proteins (LC) in vascular, cardiac, and other tissues. There is no treatment to reverse LC tissue toxicity. We tested the hypothesis that nanoliposomes composed of monosialoganglioside, phosphatidylcholine, and cholesterol (GM1 ganglioside-containing nanoliposomes [NLGM1]) can protect against LC-induced human microvascular dysfunction and assess mechanisms behind the protective effect.<br />Methods and Results: The dilator responses of ex vivo abdominal adipose arterioles from human participants without AL to acetylcholine and papaverine were measured before and after exposure to LC (20 μg/mL) with or without NLGM1 (1:10 ratio for LC:NLGM1 mass). Human umbilical vein endothelial cells were exposed for 18 to 20 hours to vehicle, LC with or without NLGM1, or NLGM1 and compared for oxidative and nitrative stress response and cellular viability. LC impaired arteriole dilator response to acetylcholine, which was restored by co-treatment with NLGM1. LC decreased endothelial cell nitric oxide production and cell viability while increasing superoxide and peroxynitrite; these adverse effects were reversed by NLGM1. NLGM1 increased endothelial cell protein expression of antioxidant enzymes heme oxygenase 1 and NAD(P)H quinone dehydrogenase 1 and increased nuclear factor, erythroid 2 like 2 (Nrf-2) protein. Nrf-2 gene knockdown reduced antioxidant stress response and reversed the protective effects of NLGM1.<br />Conclusions: NLGM1 protects against LC-induced human microvascular endothelial dysfunction through increased nitric oxide bioavailability and reduced oxidative and nitrative stress mediated by Nrf-2-dependent antioxidant stress response. These findings point to a potential novel therapeutic approach for light chain amyloidosis.<br /> (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)
- Subjects :
- Adipose Tissue blood supply
Arterioles drug effects
Arterioles physiology
Cell Survival physiology
Drug Combinations
Endothelial Cells metabolism
Gene Knockdown Techniques methods
Human Umbilical Vein Endothelial Cells
Humans
Immunoglobulin Light-chain Amyloidosis prevention & control
Male
Middle Aged
NAD(P)H Dehydrogenase (Quinone) genetics
NF-E2-Related Factor 2 genetics
Nanoparticles administration & dosage
Nitric Oxide physiology
Nitric Oxide Synthase Type III metabolism
Papaverine pharmacology
Peroxynitrous Acid biosynthesis
RNA Interference physiology
RNA, Small Interfering physiology
Reactive Oxygen Species metabolism
Superoxides metabolism
Transfection
Vascular Diseases physiopathology
Vasodilator Agents pharmacology
Cholesterol administration & dosage
Endothelium, Vascular drug effects
Gangliosides administration & dosage
Immunoglobulin Light-chain Amyloidosis complications
Phosphatidylcholines administration & dosage
Vascular Diseases prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 2047-9980
- Volume :
- 5
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of the American Heart Association
- Publication Type :
- Academic Journal
- Accession number :
- 27412900
- Full Text :
- https://doi.org/10.1161/JAHA.116.003318