Atherosclerosis (AS) 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 anti-atherosclerotic effect of ELABELA and reveal the underlying mechanisms. Plasma ELABELA levels were significantly reduced and negatively correlated with plasma MMP2 and MMP9 levels in AS patients and high-fat diet-induced atherosclerotic ApoE−/− mice. Plasma ELABELA levels exhibited a potential diagnostic value for AS patients. Application of ELABELA-21 (ELA-21) significantly decreased atherosclerotic plaque area and inflammation in the aortas from 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 and enhanced APJ, ACE, and ACE2 protein expression in plaques within aortic roots and decreased plasma sPRR levels. In vitro, ELA-21 effectively suppressed oxidized-low-density lipoprotein-induced foam cell formation and LPS/IFN-γ-induced M1 polarization in THP-1 cells. Interestingly, the anti-inflammatory effect of ELA-21 was further enhanced by APJ inhibitor ML221, accompanied by elevated ACE and ATP6AP2 and reduced ACE2 mRNA levels. Collectively, our data highlighted the diagnostic and therapeutic potential of ELABELA on AS. ELA-21 protects against AS 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 biomarker and candidate therapeutic target for treating AS.

The authors have declared no competing interest.

The studies involving human participants were reviewed and approved by the Affiliated Hospital of the Jiangxi University of Chinese Medicine (JZFYLL20230208002). We did not register the trial ID since we only collected blood samples from the peripheral veins of all patients.

This work was supported by grants from the National Natural Science Foundation of China (No. 82160051 and 32100908), the Jiangxi Provincial Natural Science Foundation (No. 20232BAB206018), the science and technology research project in Education Department of Jiangxi Province (No. GJJ2200904), Jiangxi "Double Thousand Plan" (No. jxsq2020101074), the Ph.D. Start-up Research Fund in Jiangxi University of Chinese Medicine (No. 2020BSZR009), the science and technology research project in Health Commission of Jiangxi Province (No. 202311143), Discipline of Chinese and Western Integrative Medicine in Jiangxi University of Chinese Medicine (Top Discipline of Jiangxi Province, No. zxyylxk20220103??the Scientific and Technological Innovation Team grant of the Jiangxi University of Chinese Medicine (No. CXTD22014), and the Jiangxi Key Laboratory grant in Science and Technology Department of Jiangxi Province (No.20202BCD42014).

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Ethics Committee of the Affiliated Hospital of the Jiangxi University of Chinese Medicine

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The raw data supporting the conclusions of this article will be made available by Dr. Chuanming Xu without undue reservation.