Abstract 716: Elabela Ameliorates Atherogenesis Through Restoring The M1/M2 Macrophage Balance In Apoe ^-/- Mice

Atherosclerosis is the leading cause of death in patients with cardiovascular disease worldwide. ELABELA, an early endogenous ligand for the G protein-coupled receptor APJ (apelin peptide jejunum, apelin receptor), maybe a novel therapeutic target for multiple cardiovascular diseases. The major goal of the present study was to test the potential therapeutic action of ELABELA in atherogenesis and the underlying mechanisms. ELABELA-21 (ELA-21) was used to treat low-density lipoprotein (ox-LDL)-incubated macrophages to detect macrophage foaminess. ApoE -/- mice were fed a high-fat diet (HFD) for 16 weeks and received subcutaneous injections of ELA-21 peptides (1 mg/kg/day) in the last 4 weeks to detect atherosclerotic plaque area, macrophage infiltration, and the balance between M1 and M2 macrophages. ELA-21 significantly ameliorated atherosclerosis in HFD-fed ApoE -/- mice, as characterized by significantly decreased atherosclerotic plaque area (40%, assessed by Oil-red-O staining), inhibited macrophage infiltration (45%, assessed by CD68 staining), and increased collagen content (65%, assessed by α-SMA staining). By RT-qPCR, ELA-21 treatment inhibited the mRNA expression of Icam-1 (49%), iNOS (53%), IL-1β (59%), IL-6 (55%), and Mc p-1 (80%) in the aorta of HFD-fed ApoE -/- mice. In vitro , ELA-21 treatment inhibited macrophage-derived foam cell formation (75.5%) induced by ox-LDL assessed by Oil-red-O staining. Additionally, in macrophages from the abdominal cavity of HFD-fed ApoE -/- mice, ELA-21 treatment abolished the lipid accumulation (50%) assessed by Oil-red-O staining, and modulated the balance between M1 and M2 macrophages toward a more anti-inflammatory status in HFD-fed ApoE -/- mice, as characterized by the significantly decreased mRNA levels of IL-1β (94%), Tnf-α (55%), iNOS (99%), and IL-12β (99%) (the markers of M1 macrophages), and elevated mRNA expression of Fizz1 (17777%), IL-10 (529%), and Cd206 (24%)(the markers of M2 macrophages). Collectively, our data highlighted an anti-atherosclerotic effect of ELA-21 by restoring the M1/M2 macrophage balance.