Metformin improves endothelial function in aortic tissue and microvascular endothelial cells subjected to diabetic hyperglycaemic conditions

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• 作者：Suparna Ghosh^a ; ¹ ; Arun P. Lakshmanan^a ; ¹ ; Mu Ji Hwang^b ; Haidar Kubba^b ; Ahmed Mushannen^b ; Chris R. Triggle^a ; ^b ; Hong Ding^a ; ^b ; ^{hod2005@qatar-med.cornell.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ACh ; acetylcholine ; Akt ; protein kinase B ; AMPK ; 5&prime ; AMP-activated protein kinase ; EDV ; endothelium-dependent vasodilatation ; eNOS ; endothelial nitric oxide synthase ; HG ; high glucose ; MMECs ; mouse microvascular endothelial cells ; mTOR ; mammalian target for rapamycin ; NG ; normal glucose ; peNOS ; phosphorylated endothelial nitric oxide synthase
• 刊名：Biochemical Pharmacology
• 出版年：2015
• 出版时间：1 December 2015
• 年：2015
• 卷：98
• 期：3
• 页码：412-421
• 全文大小：2352 K

文摘

The cellular mechanisms whereby metformin, the first line drug for type 2 diabetes (T2DM), mediates its antidiabetic effects remain elusive, particularly as to whether metformin has a direct protective action on the vasculature. This study was designed to determine if a brief 3-h exposure to metformin protects endothelial function against the effects of hyperglycaemia. We investigated the protective effects of metformin on endothelial-dependent vasodilatation (EDV) in thoracic aortae from T2DM db/db mice and on high glucose (HG, 40 mM) induced changes in endothelial nitric oxide synthase (eNOS) signaling in mouse microvascular endothelial cells (MMECs) in culture.

Exposure of aortae from db+/? non-diabetic control mice to high glucose (HG, 40 mM) containing Krebs for 3-h significantly (P < 0.05) reduced acetylcholine (ACh)-induced EDV compared to ACh-induced EDV in aortae maintained in normal glucose (NG, 11 mM) Krebs. The reduction of EDV was partially reversed following a 3-h exposure to 50 μM metformin; metformin also improved ACh-induced EDV in aortae from diabetic db/db mice. Immunoblot analysis of MMECs cultured in HG versus NG revealed a significant reduction of the ratio of phosphorylated (p-eNOS)/eNOS and p-Akt/Akt, but not the expression of total eNOS or Akt. The 3-h exposure of MMECs to metformin significantly (P < 0.05) reversed the HG-induced reduction in phosphorylation of both eNOS and Akt; however, no changes were detected for phosphorylation of AMPK or the expression of SIRT1.

Our data indicate that a 3-h exposure to metformin can reverse/reduce the impact of HG on endothelial function, via mechanisms linked to increased phosphorylation of eNOS and Akt.