Monosialoganglioside-Containing Nanoliposomes Restore Endothelial Function Impaired by AL Amyloidosis Light Chain Proteins. J Am Heart Assoc 2016 Jun 13;5(6)
Date
07/15/2016Pubmed ID
27412900Pubmed Central ID
PMC4937272DOI
10.1161/JAHA.116.003318Scopus ID
2-s2.0-84991523248 (requires institutional sign-in at Scopus site) 9 CitationsAbstract
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.
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.
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.
Author List
Franco DA, Truran S, Weissig V, Guzman-Villanueva D, Karamanova N, Senapati S, Burciu C, Ramirez-Alvarado M, Blancas-Mejia LM, Lindsay S, Hari P, Migrino RQAuthor
Parameswaran Hari MD Adjunct Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adipose TissueArterioles
Cell Survival
Cholesterol
Drug Combinations
Endothelial Cells
Endothelium, Vascular
Gangliosides
Gene Knockdown Techniques
Human Umbilical Vein Endothelial Cells
Humans
Immunoglobulin Light-chain Amyloidosis
Male
Middle Aged
NAD(P)H Dehydrogenase (Quinone)
NF-E2-Related Factor 2
Nanoparticles
Nitric Oxide
Nitric Oxide Synthase Type III
Papaverine
Peroxynitrous Acid
Phosphatidylcholines
RNA Interference
RNA, Small Interfering
Reactive Oxygen Species
Superoxides
Transfection
Vascular Diseases
Vasodilator Agents
