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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Role of RAGE in acute arterial injury: studies in mice with genetically ...
Role of RAGE in acute arterial injury: studies in mice with genetically manipulated levels of RAGE/RAGE function. (a–f) RAGE null mice. Lung tissue retrieved from homozygous RAGE null mice or wild-type animals was subjected to RT-PCR for detection of RAGE mRNA or Western blotting (a and b). Mice were subjected to femoral artery guide-wire injury. I/M ratio was determined on day 28 (c) and van Gieson’s elastic staining was performed on a representative femoral artery section from a wild-type mouse (d) and a RAGE null mouse (e). Scale bar: 50 μm. (f) MPO activity. One hour after injury, vessel segments were retrieved from RAGE null and wild-type mice and subjected to MPO activity assays. Vessels were harvested and pooled from n = 2 mice per condition. Data from three sets of pooled animals per condition are reported. (g–l) Tg SM22-DN-RAGE mice. Tg SM22-DN-RAGE mice were identified by Southern blotting (g). RT-PCR was performed on samples from Tg mice overexpressing full-length RAGE (lanes 1 and 2) or DN-RAGE (lanes 3 and 4). (h) Western blotting was performed on lysates retrieved from the aortae of wild-type and Tg animals (i). Immunostaining with anti-RAGE IgG of femoral artery from Tg SM22-DN-RAGE mice (k) compared with a vessel from a non-Tg littermate (j). Scale bar: 25 μm. (l) Tg SM22-DN-RAGE mice and littermates were subjected to femoral artery injury and I/M ratio was determined on day 28. In l, there were at least 10–20 vessels per experimental condition.