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AIM：To investigate the influence of fat mass and obesity-associated（Fto）gene on the aberrant contraction of aortic smooth muscle in diabetes mellitus（DM）mice，and to explore the mechanism of Fto gene underlying the calcium regulation. METHODS：Smooth muscle-specific Fto gene knockout（FtoSMKO）mice were generated using Cre-loxP technology. The experiment involved 3 groups of mice：wild-type（WT）group，DM model group and FtoSMKO-DM group，with 15 mice in each group. In DM group and FtoSMKO-DM group，type 1 DM was induced by intraperitoneal injec? tion of streptozotocin. The mice in WT group were injected with equal volume of citric acid-sodium citrate buffer solution. The influences of different drugs on the contraction responses of aortic smooth muscle in mice were analyzed using a multimyograph system. The expression level of FTO protein in the aortic tissues was detected by Western blot. RESULTS：（1）Compared with WT mice，the expression levels of FTO protein in the aortic tissues of DM mice were significantly in? creased（P<0. 01）. （2）The expression level of FTO protein in smooth muscle was significantly decreased after knockout of Fto gene（P<0. 01）. Compared with WT group，the mice in DM group exhibited a significant decrease in body weight and a marked increase in fasting blood glucose level（P<0. 05）. There were no noticeable differences in body weight or fasting blood glucose level between FtoSMKO-DM group and DM group（P>0. 05）. （3）The contraction responses of aortic smooth muscle in DM group were substantially increased by phenylephrine compared with WT group. Specifically，vaso? constriction responses mediated by non-L-type calcium channels and store-operated calcium channels（SOCC）were signifi? cantly enhanced in DM group. In addition，the responses mediated by inositol 1，4，5-trisphosphate receptors（IP3R），which facilitate calcium release from the sarcoplasmic reticulum，were significantly enhanced. However，the responses mediated by caffeine-activated ryanodine receptors（RyR），which also facilitate calcium release from the sarcoplasmic re? ticulum，were significantly inhibited（P<0. 05）. （4）Compared with DM group，the phenylephrine-induced contraction re? sponses of aortic smooth muscle in FtoSMKO-DM group were greatly weakened（P<0. 05）. In particular，the vasoconstriction responses mediated by non-L-type calcium channels and SOCC in FtoSMKO-DM group were greatly suppressed（P<0. 05），while those mediated by caffeine-activated RyR were dramatically boosted（P<0. 05）. However，IP3R-mediated responses were not affected（P>0. 05）. CONCLUSION：Smooth muscle-specific Fto gene knockout suppresses contractile hyperre? sponsiveness in the aortic smooth muscle of DM mice，which may be attributed to involvement of FTO protein in calcium regulation in the vascular smooth muscle. ? 2024 Editorial Board of Chinese Journal of Pathophysiology, Jinan University.
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