Abstract 14776: GM1 Ganglioside-containing Nanoliposomes Protect Against AL Amyloid Light Chain-induced Human Microvascular Endothelial Dysfunction
AL amyloidosis involves multiorgan tissue damage from amyloid-forming light chain proteins (LC). We previously showed the potential of phosphatidic acid-containing nanoliposomes in mitigating LC-induced vascular dysfunction. GM1 ganglioside-containing liposomes were shown to have affinity to bind amyloid proteins and may be useful in reducing LC injury.
Aim: To test the hypothesis that GM1 ganglioside-containing nanoliposomes (NLGM1) will protect against LC-induced human microvascular endothelial dysfunction.
Methods: Ex-vivo subcutaneous adipose arterioles from subjects without known vascular disease/AL were cannulated and dilator response to acetylcholine and papaverine were measured at baseline (control) and following 1-hour exposure to LC (20 μg/mL, purified from urine of 2 AL patients)± NLGM1 (1:10 LC:NLGM1 ratio; 70% cholesterol, 25% phosphatidylcholine, 5% GM1 ganglioside). Human umbilical vein endothelial cells (HUVECs) were exposed for 24 hours to LC incorporated with Oregon green fluorophore± NLGM1 and LC internalization was measured by confocal microscopy. Atomic force microscopy was used to determine interaction between LC (recombinant AL-09 derived from AL subject) and NLGM1.
Results: see Figure. There was reduced dilator response to acetylcholine following LC treatment that was reversed by NLGM1 (A; acetylcholine 10-4M dilation: C-88.1±3.4, LC+NLGM1-87.6±5.4, LC-53.0±3.8%, p≤0.001 vs. C/LC+NLGM1). NLGM1 reduced endothelial cell LC internalization (B). AFM confirmed physicochemical interaction between LC and NLGM1 (C, height NLGM1 1.85±0.14, LC 1.01±0.03, LC+NLGM1 2.76±0.2 nM, p<0.05 ANOVA and each 2 way comparison).
Conclusions: LC caused endothelial dysfunction in human arterioles that was reversed by co-treatment with NLGM1, potentially by interacting with LC and reducing endothelial cell LC internalization. NLGM1 should be further studied to determine its potential as a new therapeutic agent for AL.
Author Disclosures: S. Truran: None. V. Weissig: None. D.A. Franco: None. C. Burciu: None. S. Senapati: None. D. Guzman-Villanueva: None. S. Lindsay: None. M. Ramirez-Alvarado: Research Grant; Significant; RO1 GM 071514. P. Hari: None. R.Q. Migrino: Research Grant; Significant; VA Merit BLR&D.
- © 2014 by American Heart Association, Inc.