Abstract
Metformin exhibits diverse protective effects against diabetic complications, such as bone loss. Here, we investigated the effect of metformin on vascular calcification, another type 2 diabetes complication. In female rat aortic smooth muscle cells (RASMCs), we observed that metformin significantly alleviated β-glycerophosphate-induced Ca deposition and alkaline phosphatase activity, corresponding with reduced expression of some specific genes in osteoblast-like cells, including Runx2 and bone morphogenetic protein-2, and positive effects on α-actin expression, a specific marker of smooth muscle cells. Mechanistic analysis showed that phosphorylation levels of both AMP-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS) were increased with NO overproduction. After inhibition of either AMPK or eNOS with the pharmacologic inhibitors, compound C or Nω-Nitro-L-arginine methyl ester, NO production was lowered and metformin-meditated vascular protection against β-glycerophosphate-induced Ca deposition was removed. Our results support that metformin prevents vascular calcification via AMPK-eNOS-NO pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinases / antagonists & inhibitors
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AMP-Activated Protein Kinases / chemistry
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AMP-Activated Protein Kinases / metabolism*
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Animals
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Aorta / cytology
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Aorta / drug effects*
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Aorta / metabolism
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Aorta / pathology
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Cell Transdifferentiation / drug effects
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Cells, Cultured
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Diabetic Angiopathies / chemically induced
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Diabetic Angiopathies / metabolism
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Diabetic Angiopathies / pathology
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Diabetic Angiopathies / prevention & control
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Enzyme Activation / drug effects
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Enzyme Inhibitors / adverse effects
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Female
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Glycerophosphates / adverse effects
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Glycerophosphates / antagonists & inhibitors
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Hypoglycemic Agents / antagonists & inhibitors
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Hypoglycemic Agents / pharmacology*
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Metformin / antagonists & inhibitors
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Metformin / pharmacology*
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Muscle, Smooth, Vascular / cytology
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Muscle, Smooth, Vascular / drug effects*
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Muscle, Smooth, Vascular / metabolism
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Muscle, Smooth, Vascular / pathology
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Nitric Oxide / metabolism
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Nitric Oxide Synthase Type III / antagonists & inhibitors
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Nitric Oxide Synthase Type III / chemistry
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Nitric Oxide Synthase Type III / metabolism*
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Phosphorylation / drug effects
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Protein Kinase Inhibitors / adverse effects
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Protein Processing, Post-Translational / drug effects
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Rats
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Rats, Sprague-Dawley
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Signal Transduction / drug effects
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Vascular Calcification / chemically induced
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Vascular Calcification / metabolism
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Vascular Calcification / pathology
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Vascular Calcification / prevention & control*
Substances
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Enzyme Inhibitors
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Glycerophosphates
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Hypoglycemic Agents
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Protein Kinase Inhibitors
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Nitric Oxide
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Metformin
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Nitric Oxide Synthase Type III
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Nos3 protein, mouse
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AMP-Activated Protein Kinases
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beta-glycerophosphoric acid