Objective To explore the possible anti-atherosclerotic mechanisms of glucose co-transporter-2 inhibitor canagliflozin.Methods ApoE-/-mice fed on Western diet were randomly assigned into the model group(n=10)and the canagliflozin group(n=10).C57BL/6J mice fed on normal diet were chosen as the control group(n=10).Mice in the canagliflozin group were gavaged with canagliflozin for 14 weeks.The presence and severity of atherosclerosis were evaluated with HE and oil red O stainings in aortic root section slices.PCR assay was performed to determine the mRNA expression levels of nitric oxide synthase.Hepatic transcriptome analysis and hepatic amino acid detection were conducted using RNA-seq and targeted LC-MS,respectively.Results HE staining and oil red O staining of the aortic root showed that AS models were successfully established in ApoE-/-mice fed on Western diet for 14 weeks.Canagliflozin alleviated the severity of atherosclerosis in pathology.Hepatic transcriptome analysis indicated that canagliflozin impacted on amino acid metabolism,especially arginine synthesis in ApoE-/-mice.Targeted metabolomics analysis of amino acids showed that canagliflozin reduced hepatic levels of L-serine,L-aspartic acid,tyrosine,L-hydroxyproline,and L-citrulline,but raised the hepatic level of L-arginine.Compared to the model group,the canagliflozin group exhibited higher serum arginine and nitric oxide levels as well as elevated nitric oxide mRNA expression in aortic tissues(P＜0.05).Conclusion Canagliflozin regulated the amino acid metabolism,reduced the levels of glucogenic amino acids,and promoted the synthesis of arginine in atherosclerotic mice.
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