ELABELA Ameliorates Atherosclerosis Through Restoring the M1/M2 Macrophage Balance in ApoE^-/- Mice

Atherosclerosis is a progressive arterial disease characterized by chronic inflammation and plaque formation in blood vessel walls. ELABELA, an endogenous ligand for the G protein-coupled receptor APJ (apelin peptide jejunum, apelin receptor), has multiple pharmacological activities for protecting the cardiovascular system. This study aimed to determine the potential antiatherosclerotic effect of ELABELA and reveal the underlying mechanisms.

We enrolled a cohort consisting of patients with and without atherosclerosis to determine the relationship between plasma ELABELA levels and atherosclerosis severity. The potential therapeutic action of ELA-21 (ELABELA-21) on atherosclerosis in high-fat diet-fed ApoE^-/- mice was evaluated.

Plasma ELABELA levels were significantly reduced and negatively correlated with plasma MMP2 (matrix metallopeptidase 2) and MMP9 (matrix metallopeptidase 9) levels in patients with atherosclerosis and high-fat diet-induced atherosclerotic ApoE^-/- mice. Plasma ELABELA levels exhibited a potential diagnostic value for patients with atherosclerosis. Applying ELA-21 significantly decreased the atherosclerotic plaque area and inflammation in the aortas of the ApoE^-/- mice. ELA-21 administration modulated the balance between M1 and M2 macrophages in the abdominal cavity and aorta roots toward a more anti-inflammatory status, accompanied by reduced MMP2, MMP9, and PRR ([pro]renin receptor), and enhanced macrophage APJ, ACE (angiotensin-converting enzyme), and ACE2 (angiotensin-converting enzyme 2) protein expression in plaques within aortic roots and decreased plasma soluble PRR levels. In vitro, ELA-21 effectively suppressed oxidized low-density lipoprotein-induced foam cell formation and lipopolysaccharide/interferon-γ-induced M1 polarization in cultured macrophages. Interestingly, the anti-inflammatory effect of ELA-21 was further enhanced by APJ inhibitor ML221 [4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate], accompanied by elevated ACE and ATP6AP2 (ATPase, H⁺-transporting, lysosomal accessory protein 2) and reduced ACE2 mRNA levels.

Our data highlighted the diagnostic and therapeutic potential of ELABELA on atherosclerosis. ELA-21 protects against atherosclerosis by inhibiting atherosclerotic plaque formation and promoting a more stable plaque phenotype, possibly via restoring the M1/M2 macrophage balance, enhancing macrophage ACE and ACE2 expression, and inhibiting the PRR system. ELABELA may be a novel diagnostic biomarker and candidate therapeutic target for atherosclerosis.