Canagliflozin Inhibits Human Endothelial Cell Inflammation through the Induction of Heme Oxygenase-1.
Canagliflozin Inhibits Human Endothelial Cell Inflammation through the Induction of Heme Oxygenase-1.
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DOI：
10.3390/ijms23158777
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发表时间：
2022-08-07
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
钠-葡萄糖共转运体2(SGLT2)抑制剂改善2型糖尿病(T2 DM)患者的心血管结局。研究还表明，Canagliflzin直接作用于内皮细胞(ECs)。由于血红素氧合酶-1(HO-1)是一种公认的EC功能调节剂，我们研究了卡那格列酮是否调节HO-1的内皮表达，以及该酶是否影响卡那格列酮在这些细胞中的生物学作用。人内皮细胞经卡那格列酮处理后，HO-1的表达呈浓度和时间依赖性增加，这与HO活性的显着增加有关。Canagliflzin还可浓度依赖性地阻断EC的增殖、DNA合成和迁移，该作用不受HO-1活性和/或表达抑制的影响。内皮细胞暴露在糖尿病环境中会增加单核细胞与内皮细胞的黏附，这种黏附作用可被卡那格列酮减弱。HO-1基因的敲除降低了卡那格列酮的抗炎作用，该作用可被胆红素恢复，但不能被一氧化碳恢复。综上所述，本研究证实斑点花苷是人内皮细胞中HO-1的一种新的诱导剂。研究还发现，HO-1衍生的胆红素有助于卡那格列酮的抗炎作用，但不参与该药物的抗增殖和抗迁移作用。Canagliflzin调节HO-1表达和EC功能的能力可能有助于该药物的临床应用。
Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM). Studies have also shown that canagliflozin directly acts on endothelial cells (ECs). Since heme oxygenase-1 (HO-1) is an established modulator of EC function, we investigated if canagliflozin regulates the endothelial expression of HO-1, and if this enzyme influences the biological actions of canagliflozin in these cells. Treatment of human ECs with canagliflozin stimulated a concentration- and time-dependent increase in HO-1 that was associated with a significant increase in HO activity. Canagliflozin also evoked a concentration-dependent blockade of EC proliferation, DNA synthesis, and migration that was unaffected by inhibition of HO-1 activity and/or expression. Exposure of ECs to a diabetic environment increased the adhesion of monocytes to ECs, and this was attenuated by canagliflozin. Knockdown of HO-1 reduced the anti-inflammatory effect of canagliflozin which was restored by bilirubin but not carbon monoxide. In conclusion, this study identified canagliflozin as a novel inducer of HO-1 in human ECs. It also found that HO-1-derived bilirubin contributed to the anti-inflammatory action of canagliflozin, but not the anti-proliferative and antimigratory effects of the drug. The ability of canagliflozin to regulate HO-1 expression and EC function may contribute to the clinical profile of the drug.
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DOI：
10.2147/dmso.s154602
发表时间：
2018
期刊：
Diabetes, metabolic syndrome and obesity : targets and therapy
影响因子：
--
作者：
Cavaiola TS;Pettus J
通讯作者：
Pettus J
影响因子：
5.6
作者：
Behnammanesh, Ghazaleh;Durante, Zane E.;Durante, William
通讯作者：
Durante, William
影响因子：
3.4
作者：
Batzlsperger, Christian A.;Achatz, Stefan;Griese, Daniel P.
通讯作者：
Griese, Daniel P.
影响因子：
158.5
作者：
Duckworth, William;Abraira, Carlos;Huang, Grant D.
通讯作者：
Huang, Grant D.
影响因子：
9.2
作者：
Li Y;Wang H;Yang B;Yang J;Ruan X;Yang Y;Wakeland EK;Li Q;Fang X
通讯作者：
Fang X