Protective role of clusterin in preserving endothelial function in AL amyloidosis. Atherosclerosis 2012 Nov;225(1):220-3
Date
09/18/2012Pubmed ID
22981431Pubmed Central ID
PMC3478430DOI
10.1016/j.atherosclerosis.2012.08.028Scopus ID
2-s2.0-84867867786 (requires institutional sign-in at Scopus site) 17 CitationsAbstract
UNLABELLED: 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.
Author List
Franco DA, Truran S, Burciu C, Gutterman DD, Maltagliati A, Weissig V, 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
AmyloidosisArterioles
Cell Death
Clusterin
DNA Fragmentation
Endothelial Cells
Female
Humans
Immunoglobulin Light Chains
Male
Middle Aged
Vasodilation
