Effect of demethylase FTO knockout on 5-HT-induced abnormalities of coronary smooth muscle contractile function in mice with diabetes mellitus
- VernacularTitle:去甲基化酶FTO基因敲除对5-HT诱导糖尿病冠脉平滑肌收缩功能异常的影响
- Author:
Zi-fan WANG
1
;
Liu-xiang JIANG
;
Mei-ying LIANG
;
Meng-yun LIU
;
Mei-jiang CHEN
;
Hui YANG
;
Fang RAO
;
Chun-yu DENG
Author Information
- Publication Type:Journal Article
- Keywords: FTO gene; diabetic vasculature; m6 A methylation; non-L-type calcium channels; sarcoplas-mic reticulum calcium release; vasoconstriction
- From: Chinese Pharmacological Bulletin 2025;41(2):315-322
- CountryChina
- Language:Chinese
- Abstract: Aim To explore the influence of demethy-lase fat mass and obesity-related genes(FTO)on the abnormal contractile function of diabetic coronary smooth muscle.Methods Smooth muscle specific FTO knockout mice(FTOSMKO)were prepared by Cre-loxP recombinant technology.They were divided into four groups:control(WT)group,diabetes model group(DM),FTO knockout group(FTOSMKO),and FTOSMKO diabetic group(FTOSMKO-DM),with 15 mice in each group.Diabetic mice were prepared by intraperitoneal injection of streptozotocin(STZ);the remaining mice were injected with an equal amount of citric acid-sodi-um citrate buffer.The effects of 5-HTon the contractile response of coronary artery smooth muscle in the four groups of mice were observed by the technique of small-vessel ring tensiometry.Western blot and Dot blot were used to detect the changes of FTO protein and N6-methyladenine(m6A)methylation modification levels in mouse vascular tissues.Results Compared with the WT group,the DM group had significantly higher blood glucose(P＜0.01)and lower body weight(P＜0.05);the level of FTO protein in aorta of DM group increased(P＜0.01),and the level of m6A methylation modification decreased(P＜0.01).The 5-HT-induced contractile response significantly de-creased in the DM group compared with the WT group(P＜0.01),whereas the contractile response signifi-cantly increased in the FTOSMKO-DM group compared with the DM group(P＜0.01);the non-L-type calci-um channel-mediated vascular smooth muscle contrac-tile response was enhanced in the FTOSMKO-DM group,among which,the contractions induced by 1,4,5-triphosphate inositol receptor(IP3R)and caffeine-ac-tivated ranine receptor(RyR)mediated by sarcoplas-mic reticulum calcium release both significantly in-creased(P＜0.05).Conclusions Specific knock-down of smooth muscle FTO improves coronary artery responsiveness to the vasoconstrictor 5-HT in diabetic mice,which may be related to abnormalities in the FTO-mediated 5-HT receptor signaling pathway.
