Monosialoganglioside-containing nanoliposomes restore endothelial function impaired by AL amyloidosis light chain proteins

Daniel A. Franco, Seth Truran, Volkmar Weissig, Diana Guzman-Villanueva, Nina Karamanova, Subhadip Senapati, Camelia Burciu, Marina Ramirez-Alvarado, Luis M. Blancas-Mejia, Stuart Lindsay, Parameswaran Hari, Raymond Q. Migrino

Research output: Contribution to journalArticle

3 Scopus citations

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. 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.

Original languageEnglish (US)
Article numbere003318
JournalJournal of the American Heart Association
Volume5
Issue number6
DOIs
StatePublished - Jun 1 2016

Keywords

  • Amyloid
  • Endothelium
  • Nanotechnology
  • Oxidant stress

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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    Franco, D. A., Truran, S., Weissig, V., Guzman-Villanueva, D., Karamanova, N., Senapati, S., Burciu, C., Ramirez-Alvarado, M., Blancas-Mejia, L. M., Lindsay, S., Hari, P., & Migrino, R. Q. (2016). Monosialoganglioside-containing nanoliposomes restore endothelial function impaired by AL amyloidosis light chain proteins. Journal of the American Heart Association, 5(6), [e003318]. https://doi.org/10.1161/JAHA.116.003318