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 5

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Effect of RAGE on properties of cultured SMCs. (a–c) Aortic SMCs from wi...
Effect of RAGE on properties of cultured SMCs. (a–c) Aortic SMCs from wild-type (a), RAGE null (b), and Tg SM22-DN-RAGE mice (c) were exposed to S100b or PDGF for 10 min, and cells were harvested for phospho/total-Stat3 by Western blotting. (d–f) Cultured SMCs were added to the upper compartment of microchemotaxis chambers, and S100b was added to upper/lower compartment for 4 h (d). The migration assay was performed as in d, except that cells were preincubated with anti-RAGE IgG or nonimmune IgG. Migration was initiated by addition of either S100b or PDGF (lower compartment) (e). The migration of wild-type SMCs preincubated for 30 min with AG490 was studied as in d in the presence of S100b (5 μg/ml) (f). (g–i) Serum-starved cultured SMCs from wild-type mice were incubated with the S100b for 2 days, and DNA synthesis was quantitated by 3H-incorporation (g). SMCs cultured from RAGE null or Tg SM22-DN-RAGE mice were exposed to S100b or PDGF (g). The assay was performed as in g (wild-type SMCs), except that anti-RAGE IgG or nonimmune IgG was added, and cultures were exposed to S100b or PDGF (h). Cultured SMCs from wild-type mice were exposed to S100b in the presence of AG490, and 3H-thymidine incorporation was determined (i). (j) SMCs from wild-type mice were exposed to S100b for 12 h, and RNA was harvested for RT-PCR using primers for tenascin-C or β-actin.