Faculty Collaboration Database

CD36 participates in a signaling pathway that regulates ROS formation in murine VSMCs. J Clin Invest 2010 Nov;120(11):3996-4006

Date

10/28/2010

Pubmed ID

20978343

Pubmed Central ID

PMC2964976

DOI

10.1172/JCI42823

Scopus ID

2-s2.0-78049420726 (requires institutional sign-in at Scopus site)   115 Citations

Abstract

CD36 is a membrane glycoprotein expressed on platelets, monocytes, macrophages, and several other cell types that was recently demonstrated to be involved in platelet activation in response to oxidized phospholipids, including oxidized LDL. Although the role of CD36 in other vascular cells has not been well defined, previous studies have demonstrated that cd36-knockout (cd36-/-) mice have prolonged thrombosis times after vascular injury, which can be protective in the state of hyperlipidemia. Here, we found significantly less ROS in the vessel walls of cd36-/- mice compared with WT after chemically induced arterial injury, suggesting that CD36 may contribute to ROS generation in the VSMCs themselves. Gene expression analysis revealed that the antioxidant enzymes peroxiredoxin-2 (Prdx2) and heme oxygenase-1 were upregulated in cd36-/- VSMCs. Molecular dissection of the pathway in isolated mouse VSMCs revealed CD36 ligand-dependent induction of Fyn phosphorylation, with subsequent phosphorylation and degradation of the redox-sensitive transcription factor Nrf2. Chromatin immunoprecipitation experiments further showed that Nrf2 directly occupied the Prdx2 promoter. The importance of this pathway was evidenced by increased ROS generation in prdx2-/- mice and decreased thrombosis times in both prdx2-/- and nrf2-/- mice after vascular injury. These data suggest that CD36-mediated downregulation of antioxidant systems in VSMCs may contribute to its prothrombotic, proinflammatory, and atherogenic effects.

Author List

Li W, Febbraio M, Reddy SP, Yu DY, Yamamoto M, Silverstein RL

Author

Roy L. Silverstein MD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Active Transport, Cell Nucleus
Animals
Antioxidants
CD36 Antigens
Carotid Arteries
Male
Mice
Mice, Knockout
Muscle, Smooth, Vascular
Myocytes, Smooth Muscle
NF-E2-Related Factor 2
Peroxiredoxins
Promoter Regions, Genetic
Proto-Oncogene Proteins c-fyn
Reactive Oxygen Species
Signal Transduction