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Metformin inhibits vascular calcification in female rat aortic smooth muscle cells via the AMPK-eNOS-NO pathway.

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.
AuthorsXiaorui Cao, Huan Li, Huiren Tao, Ning Wu, Lifeng Yu, Dawei Zhang, Xiaozhao Lu, Jinyu Zhu, Zifan Lu, Qingsheng Zhu
JournalEndocrinology (Endocrinology) Vol. 154 Issue 10 Pg. 3680-9 (Oct 2013) ISSN: 1945-7170 [Electronic] United States
PMID24025223 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Enzyme Inhibitors
  • Glycerophosphates
  • Hypoglycemic Agents
  • Protein Kinase Inhibitors
  • Nitric Oxide
  • Metformin
  • Nitric Oxide Synthase Type III
  • Nos3 protein, mouse
  • AMP-Activated Protein Kinases
  • beta-glycerophosphoric acid
Topics
  • AMP-Activated Protein Kinases (antagonists & inhibitors, chemistry, metabolism)
  • Animals
  • Aorta (cytology, drug effects, metabolism, pathology)
  • Cell Transdifferentiation (drug effects)
  • Cells, Cultured
  • Diabetic Angiopathies (chemically induced, metabolism, pathology, prevention & control)
  • Enzyme Activation (drug effects)
  • Enzyme Inhibitors (adverse effects)
  • Female
  • Glycerophosphates (adverse effects, antagonists & inhibitors)
  • Hypoglycemic Agents (antagonists & inhibitors, pharmacology)
  • Metformin (antagonists & inhibitors, pharmacology)
  • Muscle, Smooth, Vascular (cytology, drug effects, metabolism, pathology)
  • Nitric Oxide (metabolism)
  • Nitric Oxide Synthase Type III (antagonists & inhibitors, chemistry, metabolism)
  • Phosphorylation (drug effects)
  • Protein Kinase Inhibitors (adverse effects)
  • Protein Processing, Post-Translational (drug effects)
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction (drug effects)
  • Vascular Calcification (chemically induced, metabolism, pathology, prevention & control)

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