Cellular response of cardiac fibroblasts to amyloidogenic light chains

Vickery Trinkaus-Randall, Mary T. Walsh, Shawn Steeves, Grace Monis, Lawreen H. Connors, Martha Skinner

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Amyloidoses are a group of disorders characterized by abnormal folding of proteins that impair organ function. We investigated the cellular response of primary cardiac fibroblasts to amyloidogenic light chains and determined the corresponding change in proteoglycan expression and localization. The cellular response to 11 urinary immunoglobulin light chains of κ1, λ6, and λ 3 subtypes was evaluated. The localization of the light chains was monitored by conjugating them to Oregon Green 488 and performing live cell confocal microscopy. Sulfation of the proteoglycans was determined after elution over Q1-columns with a single-step salt gradient (1.5 mol/L NaCl) via dimethylmethylene blue. Light chains were detected inside cells within 4 hours and demonstrated perinuclear localization. Over 80% of the cells showed intracellular localization of the amyloid light chains. The light chains induced sulfation of the secreted glycosaminoglycans, but the cell fraction possessed only minimal sulfation. Furthermore, the light chains caused a translocation of heparan sulfate proteoglycan to the nucleus. The conformation and thermal stability of light chains was altered when they were incubated in the presence of heparan sulfate and destabilization of the amyloid light chains was detected. These studies indicate that internalization of the light chains mediates the expression and localization of heparan sulfate proteoglycans.

Original languageEnglish (US)
Pages (from-to)197-208
Number of pages12
JournalAmerican Journal of Pathology
Volume166
Issue number1
DOIs
StatePublished - Jan 1 2005
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Trinkaus-Randall, V., Walsh, M. T., Steeves, S., Monis, G., Connors, L. H., & Skinner, M. (2005). Cellular response of cardiac fibroblasts to amyloidogenic light chains. American Journal of Pathology, 166(1), 197-208. https://doi.org/10.1016/S0002-9440(10)62244-4