Central role of RAGE-dependent neointimal expansion in arterial restenosis
Taichi Sakaguchi, Shi Fang Yan, Shi Du Yan, Dmitri Belov, Ling Ling Rong, Monica Sousa, Martin Andrassy, Steven P. Marso, Stephan Duda, Bernd Arnold, Birgit Liliensiek, Peter P. Nawroth, David M. Stern, Ann Marie Schmidt, Yoshifumi Naka
Taichi Sakaguchi, Shi Fang Yan, Shi Du Yan, Dmitri Belov, Ling Ling Rong, Monica Sousa, Martin Andrassy, Steven P. Marso, Stephan Duda, Bernd Arnold, Birgit Liliensiek, Peter P. Nawroth, David M. Stern, Ann Marie Schmidt, Yoshifumi Naka
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Article Cardiology

Central role of RAGE-dependent neointimal expansion in arterial restenosis

Abstract

Cellular proliferation, migration, and expression of extracellular matrix proteins and MMPs contribute to neointimal formation upon vascular injury. Wild-type mice undergoing arterial endothelial denudation displayed striking upregulation of receptor for advanced glycation end products (RAGE) in the injured vessel, particularly in activated smooth muscle cells of the expanding neointima. In parallel, two of RAGE’s signal transducing ligands, advanced glycation end products (AGEs) and S100/calgranulins, demonstrated increased deposition/expression in the injured vessel wall. Blockade of RAGE, employing soluble truncated receptor or antibodies, or in homozygous RAGE null mice, resulted in significantly decreased neointimal expansion after arterial injury and decreased smooth muscle cell proliferation, migration, and expression of extracellular matrix proteins. A critical role for smooth muscle cell RAGE signaling was demonstrated in mice bearing a transgene encoding a RAGE cytosolic tail-deletion mutant, specifically in smooth muscle cells, driven by the SM22α promoter. Upon arterial injury, neointimal expansion was strikingly suppressed compared with that observed in wild-type littermates. Taken together, these data highlight key roles for RAGE in modulating smooth muscle cell properties after injury and suggest that RAGE is a logical target for suppression of untoward neointimal expansion consequent to arterial injury.

Authors

Taichi Sakaguchi, Shi Fang Yan, Shi Du Yan, Dmitri Belov, Ling Ling Rong, Monica Sousa, Martin Andrassy, Steven P. Marso, Stephan Duda, Bernd Arnold, Birgit Liliensiek, Peter P. Nawroth, David M. Stern, Ann Marie Schmidt, Yoshifumi Naka

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Figure 6

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Effect of sRAGE on neointimal expansion in apoE null mice. (a–h) ApoE nu...
Effect of sRAGE on neointimal expansion in apoE null mice. (a–h) ApoE null mice were subjected to femoral artery guide-wire injury (day 1), and animals were treated with either sRAGE or MSA (100 μg/day, intraperitoneally, days 0–7) and sacrificed on day 28. Representative sections were treated with van Gieson’s elastic stain (a and b) or subjected to immunohistochemistry with anti-F4/80 IgG (d–g). The I/M ratio was determined on day 28 in the two groups of mice (c). (h) For 4/80-stained sections, image analysis was performed, and the area occupied by immunoreactive cells in the neointima and media was determined. These experiments employed at least eight vessels for each experimental condition, and the experiment was repeated twice. Scale bars: a, b, d, and f, 50 μm, and e and g, 25 μm.