Activation of Nrf2 by dimethyl fumarate improves vascular calcification.

Abstract

Dimethyl fumarate (DMF) has several pharmacological benefits including immunomodulation and prevention of fibrosis, which are dependent on the NF-E2-related factor 2 (Nrf2) antioxidant pathways. Therefore, we hypothesized that DMF could attenuate vascular calcification via Nrf2 activation. Vascular calcification induced by hyperphosphataemia was significantly inhibited by DMF in vascular smooth muscle cells (VSMCs) in a dose-dependent manner. DMF-mediated Nrf2 upregulation was accompanied by the reduced expressions of genes related with osteoblast-like phenotype based on promoter activity, mRNA and protein expression, and von Kossa staining. Likewise, Nrf2 overexpression significantly decreased the formation of calcium deposit similar to the level of osteogenic staining in VSMCs, and DMF with Nrf2 knockdown failed to attenuate hyperphosphatemia induced vascular calcification. Furthermore, DMF significantly attenuated the calcification of ex vivo ring culture from both rat common carotid artery and mouse thoracic aorta as well as in vivo mouse model of Vitamin D3-induced calcification consistent with the increased Nrf2 protein levels in early stage of calcification by DMF. In conclusion, our data support that DMF stimulates Nrf2 activity to attenuate hyperphosphatamia in vitro or Vitamin D3-induced in vivo vascular calcification, which would be a beneficial effect on vascular diseases induced by oxidative stress such as vascular calcification.

• Authors: Chae-Myeong Ha, Sungmi Park, Young-Keun Choi, Ji-Yun Jeong, Chang Joo Oh, Kwi-Hyun Bae, Sun Joo Lee, Ji-Hyun Kim, Keun-Gyu Park, Do Youn Jun, In-Kyu Lee
• Journal: Vascular pharmacology (Vascul Pharmacol) Vol. 63 Issue 1 Pg. 29-36 (Oct 2014) ISSN: 1879-3649 [Electronic] United States
• PMID: 25135648 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Fumarates
• NF-E2-Related Factor 2
• RNA, Messenger
• Dimethyl Fumarate
• Calcium

Topics

• Animals
• Aorta, Thoracic (drug effects, pathology)
• Calcium (metabolism)
• Carotid Artery, Common (drug effects, pathology)
• Dimethyl Fumarate
• Dose-Response Relationship, Drug
• Fumarates (administration & dosage, pharmacology)
• Gene Expression Regulation (drug effects)
• Humans
• Male
• Mice
• Mice, Inbred C57BL
• Muscle, Smooth, Vascular (cytology, drug effects)
• Myocytes, Smooth Muscle (drug effects, metabolism)
• NF-E2-Related Factor 2 (metabolism)
• Oxidative Stress (drug effects)
• RNA, Messenger (metabolism)
• Rats
• Rats, Sprague-Dawley
• Up-Regulation (drug effects)
• Vascular Calcification (drug therapy, pathology)