Multi-omics analysis identified spermidine as a potential compound against aortic aneurysm rupture

<h2>Abstract</h2> Abdominal aortic aneurysm (AAA) is a life-threatened aortic disease with a high mortality rate in case of rupture, accompanied by abnormalities in metabolic processes. However, how polyamine metabolism is involved in AAA development remains largely unknown. Single-cell RNA sequencing (scRNA-seq) analysis revealed a higher activity of polyamine metabolism pathway in multiple cell clusters within human AAA compared to nonaneurysmal samples. The mRNA expression levels of genes related to polyamine metabolism, such as ODC1 and SAT1, were also found to be elevated in various cell clusters of human AAA samples. Immunofluorescence assays confirmed an increased expression of ODC1 in AAA tissues relative to controls. Polyamine metabolomic analysis indicated that spermidine (SPD) levels were positively correlated with the diameters of AAA (R=0.73, <i>P</i>=0.04). In Angiotensin II (Ang II)-induced AAA model of Apoe-/- mice, SPD treatment significantly reduced the incidence of aneurysm rupture compared to the control group (27 % vs 62.5 %, <i>P</i><0.0001). ScRNA-seq of mouse aortic aneurysm tissues revealed a higher proportion of smooth muscle cells (SMCs) in the SPD-treated groups. Trajectory analysis suggested that the clusters of SMCs underwent the phenotype switch from the contractile SMCs to synthetic SMCs. Differential expressed gene analysis in the SMCs cluster showed that elastin (Eln) mRNA is the most markedly upregulated gene in SPD-treated group compared to controls. In both PPE-induced AAA mouse models and mouse vascular smooth muscle cell (MOVAS), Eln mRNA levels were significantly increased in SPD-treated groups than in control groups. We found that polyamine metabolism is more active in AAA. As one of polyamines, SPD can prevent rupture of aortic aneurysms. Eln upregulation by SPD in SMCs may be the potential molecular mechanism.