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

ROMINA GISONNO; GRACIELA CALABRESE; ANA CLARA EIGUREN; ALEJANDRA TRICERRI; ROSU SILVANA; NAHUEL ALBERTO RAMELLA

Mar del Plata

Congreso; LXIV Reunión Anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2019

Sociedad argentina de investigaciones clínicas

The cascade of molecular events leading tohuman apolipoprotein A?I (apoA?I) amyloidosis is not completelyunderstood, not even the pathways that determine clinicalmanifestations associated to systemic protein deposition inorgans such as liver, kidney and heart. Among more than twentynatural variants of apoA-I, it was shown that the substitution ofan Arg in position 173 by a Pro in the sequence of apoA-I(R173P) induced heart amyloidosis. The mechanisms determiningits pathogenicity are not clear. In this work we gained deepinsight into cellular events probably elicited by the solubleconformation of R173P. WT apoA-I and R173P were obtained bymolecular biology techniques. Human umbilical vein endothelialcells (HUVEC) or a human monocyte-derived cellular line (THP-1)were treated with 1.5 μg/ml for 24 h. Immunofluorescence ofNFkB was used to evaluate endothelial activation; and enzymeimmunoassays (ELISA) were performed to evaluate tumornecrosis factor (TNF) alpha; and interleukin (IL)-1ß. We detectedthat the natural variant R173 induced NFkB translocation into thenucleus of endothelial cells. Moreover, the incubation of R173Pwith THP-1 resulted in the release of tumor necrosis TNF- alpha(p<0.001), and IL-1ß (p<0.0001), 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 thepathological mechanisms of R173 variant may be to promote aninflammatory microenvironment which could in turn result inendothelial dysfunction.