title: Protective role of clusterin in preserving endothelial function in AL amyloidosis.
abstract: Misfolded immunoglobulin light chain proteins (LC) in light chain amyloidosis (AL) are toxic to vascular tissues. We tested the hypothesis that chaperone protein clusterin preserves endothelial function and cell survival during LC exposure.
  
  
  METHODS
  LC (20 μg/mL) were given to human aortic endothelial cells (EC) for 24-h and clusterin protein/gene expression and secretion were measured. DNA fragmentation was measured with/without recombinant clusterin (Clu, 300 ng/mL). Adipose arterioles (non-AL subjects) were tested for dilator responses to acetylcholine/papaverine at baseline and after 1-h of LC ± Clu.
  
  
  RESULTS
  LC reduced EC clusterin secretion, protein and gene expression while increasing DNA fragmentation. Clu attenuated LC-induced DNA fragmentation and restored dilator response to acetylcholine (logEC50: control -7.05 ± 0.2, LC + Clu -6.53 ± 0.4, LC -4.28 ± 0.7, p < 0.05 versus control, LC + Clu).
  
  
  CONCLUSIONS
  LC induced endothelial cell death and dysfunction while reducing clusterin protein/gene expression and secretion. Exogenous clusterin attenuated LC toxicity. This represents a new pathobiologic mechanism and therapeutic target for AL amyloidosis.
authors.affiliation: Phoenix Veterans Affairs Health Care System, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Franco
authors.forename: Seth
authors.initials: S
authors.lastname: Truran
authors.forename: Camelia
authors.initials: C
authors.lastname: Burciu
authors.forename: David D
authors.initials: DD
authors.lastname: Gutterman
authors.forename: Anthony
authors.initials: A
authors.lastname: Maltagliati
authors.forename: Volkmar
authors.initials: V
authors.lastname: Weissig
authors.forename: Parameswaran
authors.initials: P
authors.lastname: Hari
authors.forename: Raymond Q
authors.initials: RQ
authors.lastname: Migrino
mesh_terms: D000686:Amyloidosis / Q000503:physiopathology*; D001160:Arterioles / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects; D051152:Clusterin / Q000096:biosynthesis / Q000502:physiology*; D053938:DNA Fragmentation / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D014664:Vasodilation / Q000187:drug effects
chemical_list: D051152:Clusterin; D007147:Immunoglobulin Light Chains