Libro de resumenes Gordon Conference - MASR-MRGDR HETEROMERIZATION MEDIATES THE ANTI-INFLAMMATORY RESPONSE OF ALAMANDINE IN HUMAN MACROPHAGES

Congress

Summary *

The renin-angiotensin system is composed of the pressor axis, consisting of angiotensin (Ang) II and the receptor (R) AT1 that mediates the pressor and trophic effects of Ang II, and the depressor axis represented by Ang-(1-7) and MasR as the mediator of the vasodilatory, anti-inflammatory and antifibrotic effects of Ang-(1-7). Alamandine (ALA), a new component of this system, exerts effects similar to those of angiotensin (Ang) (1-7) through the stimulation of a receptor (R) distinct from MasR, the Mas-related G protein-coupled receptor type D receptor (MrgDR). Alamandine (ALA) exerts protective effects similar to those of angiotensin (1–7) through the stimulation of Mas-related G protein-coupled receptor type D receptor (MrgDR), which is distinct from Mas receptor (MasR). ALA induces anti-inflammatory effects in mice but evidence in human macrophages is lacking. We investigated the anti-inflammatory effects of ALA in human macrophages and the involvement of MasR–MrgDR heteromerization in its response. Interleukin (IL)-6 and IL-1β were measured by ELISA in human THP-1 macrophages and human monocyte-derived macrophages exposed to lipopolysaccharide (LPS). MasR–MrgDR heteromerization was investigated in transfected HEK293T cells. ALA decreased IL-6 and IL-1β secretion in human LPS-activated THP-1 macrophages. The ALA-induced decrease in IL-6 but not IL-1β was prevented by MasR blockade and MasR downregulation, suggesting MasR–MrgDR interaction. ALA did not decrease IL-6 but did decrease IL-1β in human monocyte-derived macrophages; this effect was not modified by MasR blockade. MasR–MrgDR interaction was confirmed in THP-1 macrophages, human monocyte-derived macrophages, and transfected HEK293T cells. MasR and MrgDR formed a constitutive heteromer that was not influenced by ALA. ALA promoted Akt and ERK1/2 activation only in cells expressing MasR–MrgDR heteromers, and this effect was prevented by MasR blockade. ALA decreased cellular proliferation in cells expressing MasR–MrgDR heteromers but not in cells expressing MrgDR. The antiproliferative effect of ALA was also observed in human THP-1 cells, and this effect was prevented by MasR blockade, reinforcing MasR–MrgDR interaction. We conclude that MasR–MrgDR heteromerization mediates the ALA-induced decrease in cellular proliferation and IL-6 secretion but not IL-1β secretion in human macrophages. Information provided by the agent in SIGEVA