Stimulation of inflammatory microenvironment by a human apolipoprotein A-I natural variant

GISONNO, R.; EIGUREN, A.C.; ROSÚ, S A.; CALABRESE G; TRICERRI, M. A.; RAMELLA, N.

buenos aires

Congreso; Encuentro conjunto de las sociedades S A I C, S A F E, S A B, SAP; 2019

Sociedad Argentina de Investigaciones clínicas

The cascade of molecular events leading to human apolipoprotein A?I (apoA?I) amyloidosis is not completely understood, not even the pathways that determine clinical manifestations associated to systemic protein deposition in organs such as liver, kidney and heart. Among more than twenty natural variants of apoA-I, it was shown that the substitution of an Arg in position 173 by a Pro in the sequence of apoA-I (R173P) induced heart amyloidosis. The mechanisms determining its pathogenicity are not clear. In this work we gained deep insight into cellular events probably elicited by the soluble conformation of R173P. WT apoA-Iand R173P were obtained by molecular biology techniques. Human umbilical vein endothelial cells (HUVEC) or a human monocyte-derived cellular line (THP-1) were treated with 1.5 µg/ml for 24hs. Immunofluorescence of NFκB and zymographic analysis were used to evaluate endothelial activation. We detected that the natural variant R173 induced NFκB translocation into the nucleus with a significative release of the inflammatory matrix metalloproteinase- 9. Moreover, the incubation of R173P with THP-1 resulted in the release of tumor necrosis factor (TNF)- α and interleukin (IL)-1 β without affecting cell viability. On the other hand, WT apoA-I did not show the mentioned events. These findings suggest that at least part of the pathological mechanisms of R173 variant may be to promote an inflammatory microenvironment which could in turn result in endothelial dysfunction.