title: Monosialoganglioside-Containing Nanoliposomes Restore Endothelial Function Impaired by AL Amyloidosis Light Chain Proteins.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Phoenix Veterans Affairs Health Care System, Phoenix, AZ.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Franco
authors.affiliation: Phoenix Veterans Affairs Health Care System, Phoenix, AZ.
authors.forename: Seth
authors.initials: S
authors.lastname: Truran
authors.affiliation: Midwestern University, Glendale, AZ.
authors.forename: Volkmar
authors.initials: V
authors.lastname: Weissig
authors.affiliation: Midwestern University, Glendale, AZ.
authors.forename: Diana
authors.initials: D
authors.lastname: Guzman-Villanueva
authors.affiliation: Phoenix Veterans Affairs Health Care System, Phoenix, AZ.
authors.forename: Nina
authors.initials: N
authors.lastname: Karamanova
authors.affiliation: Arizona State University, Tempe, AZ.
authors.forename: Subhadip
authors.initials: S
authors.lastname: Senapati
authors.affiliation: Phoenix Veterans Affairs Health Care System, Phoenix, AZ.
authors.forename: Camelia
authors.initials: C
authors.lastname: Burciu
authors.affiliation: Mayo Clinic, Rochester, MN.
authors.forename: Marina
authors.initials: M
authors.lastname: Ramirez-Alvarado
authors.affiliation: Mayo Clinic, Rochester, MN.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Blancas-Mejia
authors.affiliation: Arizona State University, Tempe, AZ.
authors.forename: Stuart
authors.initials: S
authors.lastname: Lindsay
authors.affiliation: Medical College of Wisconsin, Milwaukee, WI.
authors.forename: Parameswaran
authors.initials: P
authors.lastname: Hari
authors.affiliation: Phoenix Veterans Affairs Health Care System, Phoenix, AZ University of Arizona College of Medicine, Phoenix, AZ raymond.migrino@va.gov.
authors.forename: Raymond Q
authors.initials: RQ
authors.lastname: Migrino
mesh_terms: D000273:Adipose Tissue / Q000098:blood supply; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000502:physiology; D002784:Cholesterol / Q000008:administration & dosage*; D004338:Drug Combinations; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects*; D005732:Gangliosides / Q000008:administration & dosage*; D055785:Gene Knockdown Techniques / Q000379:methods; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D000075363:Immunoglobulin Light-chain Amyloidosis / Q000150:complications* / Q000517:prevention & control; D008297:Male; D008875:Middle Aged; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D053758:Nanoparticles / Q000008:administration & dosage; D009569:Nitric Oxide / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010208:Papaverine / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000096:biosynthesis; D010713:Phosphatidylcholines / Q000008:administration & dosage*; D034622:RNA Interference / Q000502:physiology; D034741:RNA, Small Interfering / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism; D014162:Transfection; D014652:Vascular Diseases / Q000503:physiopathology / Q000517:prevention & control*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D004338:Drug Combinations; D005732:Gangliosides; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D010713:Phosphatidylcholines; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D014665:Vasodilator Agents; C025447:sialogangliosides; D013481:Superoxides; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; D002784:Cholesterol; D010208:Papaverine; D052250:Nitric Oxide Synthase Type III; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human
keywords: amyloid; endothelium; nanotechnology; oxidant stress