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Abstract: Adrenomedullin (ADM) is a multifunctional peptide regulating cardiovascular homeostasis. We studied the role of ADM in the pathogenesis of atherosclerosis by investigating changes in ADM and its receptors – calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMPs) – in aorta of apoE−/− mice and the effect of exogenous ADM administration. ApoE−/− mice were fed an atherogenic diet for 4 weeks, and apoE−/−+ADM mice were additionally given subcutaneous injections of ADM, 300ng/kg/h, for 4 weeks. ApoE−/− mice fed an atherogenic diet showed hyperlipidemia, a large plaque area and increased vessel wall thickness. The mRNA expression and protein level of ADM/ADM receptors were increased in the aorta, compared with C57BL/6J mice. The elevated mRNA level of CRLR and RAMPs correlated positively with ADM mRNA level. Radioimmunoassay revealed a higher plasma and aorta ADM content, by 61.6% and 285% (both P <0.01), respectively, in apoE−/− mice than that in C57BL/6J mice. Exogenous ADM significantly ameliorated dyslipidemia in apoE−/− mice. ADM-treated mice showed fewer aortic plaques, decreased plaque area, by 76% (P <0.01), and reduced ratio of plaque area to luminal area, by 65% (P <0.01), and ultrasonography revealed significantly reduced intima-media thickness of the ascending branch and abdominal aorta. The results suggest that atherosclerotic apoE−/− mice fed an atherogenic diet showed upregulated endogenous ADM and its receptors, and exogenous ADM treatment ameliorated the dyslipidemia and vascular atherosclerotic lesions. ADM/ADM receptors might be an important protective system against atherosclerosis and could become a new target of prevention and therapy for atherosclerosis. [Copyright &y& Elsevier]