Metformin attenuates fluctuating glucose-induced endothelial dysfunction through enhancing GTPCH1-mediated eNOS recoupling and inhibiting NADPH oxidase.

AIMS The aim of this study was to investigate whether and how metformin ameliorated endothelial dysfunction induced by fluctuating glucose (FG) in human umbilical vein endothelial cells (HUVECs). METHODS HUVECs, which were exposed to FG to induce endothelial dysfunction, were incubated with nitric oxide synthase (NOS) inhibitor N-nitro-l-arginine-methyl ester (l-NAME), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor apocynin, metformin and/or adenosine monophosphate-activated protein kinase (AMPK) inhibitor compound C. The oxidative stress and endothelial NOS (eNOS) coupling were evaluated. RESULTS FG induced endothelial dysfunction as indicated by increased reactive oxygen species (ROS) generation and decreased nitric oxide (NO) production. Although FG increased eNOS phosphorylation, uncoupled eNOS was evidenced by downregulated guanosine 5'-triphosphate cyclohydrolase 1 (GTPCH1) and tetrahydrobiopterin (BH4) levels. FG also upregulated the level of p47-phox, a subunit of NADPH oxidase. Similar to l-NAME and apocynin, metformin ameliorated the FG-induced endothelial dysfunction by decreasing ROS generation. Furthermore, metformin recoupled eNOS through upregulating GTPCH1 and BH4 levels, and attenuated the upregulation of p47-phox in FG-treated HUVECs. Addition of compound C abolished the above effects of metformin. CONCLUSION Metformin improves the FG-induced endothelial dysfunction in HUVECs. The protective effect of metformin may be mediated through activation of GTPCH1-mediated eNOS recoupling and inhibition of NADPH oxidase via an AMPK-dependent pathway.

• Publication year

  2016

• Venue

  Journal of diabetes and its complications

• Publication date

  2016-08-01

• Fields of study

  Medicine

• Identifiers
  DOI 10.1016/j.jdiacomp.2016.04.018PMID 27217019
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2013cited by this paper
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  2011influential reference
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  2011cited by this paper
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  2009cited by this paper
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