title: Metformin improves endothelial function in aortic tissue and microvascular endothelial cells subjected to diabetic hyperglycaemic conditions.
abstract: 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.
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College in Qatar, P.O. Box 24144, Education City, Doha, Qatar.
authors.forename: Suparna
authors.initials: S
authors.lastname: Ghosh
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College in Qatar, P.O. Box 24144, Education City, Doha, Qatar.
authors.forename: Arun P
authors.initials: AP
authors.lastname: Lakshmanan
authors.affiliation: Medical Education, Weill Cornell Medical College in Qatar, P.O. Box 24144, Education City, Doha, Qatar.
authors.forename: Mu Ji
authors.initials: MJ
authors.lastname: Hwang
authors.affiliation: Medical Education, Weill Cornell Medical College in Qatar, P.O. Box 24144, Education City, Doha, Qatar.
authors.forename: Haidar
authors.initials: H
authors.lastname: Kubba
authors.affiliation: Medical Education, Weill Cornell Medical College in Qatar, P.O. Box 24144, Education City, Doha, Qatar.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Mushannen
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College in Qatar, P.O. Box 24144, Education City, Doha, Qatar; Medical Education, Weill Cornell Medical College in Qatar, P.O. Box 24144, Education City, Doha, Qatar.
authors.forename: Chris R
authors.initials: CR
authors.lastname: Triggle
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College in Qatar, P.O. Box 24144, Education City, Doha, Qatar; Medical Education, Weill Cornell Medical College in Qatar, P.O. Box 24144, Education City, Doha, Qatar. Electronic address: hod2005@qatar-med.cornell.edu.
authors.forename: Hong
authors.initials: H
authors.lastname: Ding
mesh_terms: D000263:Adenylate Kinase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D055785:Gene Knockdown Techniques; D006943:Hyperglycemia / Q000150:complications / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000187:drug effects* / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D052250:Nitric Oxide Synthase Type III; D000263:Adenylate Kinase
keywords: Akt; Aorta; Diabetes; Endothelial cells; Metformin; eNOS