Smad and p38 MAP kinase-mediated signaling of proteoglycan synthesis in vascular smooth muscle

Dadlani, Harsha, Ballinger, Mandy L., Osman, Narin, Getachew, Robel and Little, Peter J. (2008) Smad and p38 MAP kinase-mediated signaling of proteoglycan synthesis in vascular smooth muscle. Journal of Biological Chemistry, 283 12: 7844-7852. doi:10.1074/jbc.M703125200

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Author Dadlani, Harsha
Ballinger, Mandy L.
Osman, Narin
Getachew, Robel
Little, Peter J.
Title Smad and p38 MAP kinase-mediated signaling of proteoglycan synthesis in vascular smooth muscle
Journal name Journal of Biological Chemistry   Check publisher's open access policy
ISSN 0021-9258
1083-351X
Publication date 2008-03-21
Sub-type Article (original research)
DOI 10.1074/jbc.M703125200
Open Access Status File (Publisher version)
Volume 283
Issue 12
Start page 7844
End page 7852
Total pages 9
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Language eng
Abstract Atherosclerosis is the underlying pathological process of most cardiovascular disease. A critical component of the "response to retention" hypothesis of atherogenesis is proteoglycan/low density lipoprotein (LDL) binding. Transforming growth factor β (TGF-β) is present in atherosclerotic lesions, regulates vascular smooth muscle cell (VSMC) proteoglycan synthesis via an unknown signaling pathway, and increases proteoglycan/LDL binding. This pathway was investigated using the activin receptor-like kinase 5 (ALK5) inhibitor SB431542 and inhibitors of p38 MAP kinase as a possible downstream or alternative mediator. TGF-β stimulated and SB431542 inhibited the phosphorylation of Smad2/3. In human VSMC, TGF-β increased [ 35S]sulfate incorporation into proteoglycans associated with a 19% increase in glycosaminoglycan (GAG) chain size by size exclusion chromatography. SB431542 caused a concentration-dependent decrease in TGF-β-mediated [ 35S]sulfate incorporation with 92% inhibition at 3 μM. Two different p38 MAP kinase inhibitors, SB203580 and SB202190, but not the inactive analogue SB202474, concentration dependently blocked TGF-β-mediated [ 35S]sulfate incorporation. TGF-β increased [ 3H]glucosamine incorporation into glycosaminoglycans by 180% and [ 35S]Met/Cys incorporation into proteoglycan core proteins by 35% with both effects completely inhibited by SB431542. Blocking both Smad2/3 and p38 MAP kinase pathways prevented the effect of TGF-β to increase proteoglycan to LDL binding. TGF-β mediates its effects on proteoglycan synthesis in VSMCs via the ALK5/Smad2/3 phosphorylation pathway as well as via the p38 MAP kinase signaling cascade. Further studies of downstream pathways controlling proteoglycan synthesis may identify potential therapeutic targets for the prevention of atherosclerosis and cardiovascular disease.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Pharmacy Publications
 
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