Central role of RAGE-dependent neointimal expansion in arterial restenosis
Taichi Sakaguchi, … , Ann Marie Schmidt, Yoshifumi Naka
Taichi Sakaguchi, … , Ann Marie Schmidt, Yoshifumi Naka
Published April 1, 2003
Citation Information: J Clin Invest. 2003;111(7):959-972. https://doi.org/10.1172/JCI17115.
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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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Mechanisms underlying sRAGE-mediated suppression of neointimal expansion...
Mechanisms underlying sRAGE-mediated suppression of neointimal expansion in wild-type mice. (a) BrdU-labeling index. Mice were subjected to femoral artery guide-wire injury followed by intraperitoneal injection of BrdU and sacrifice on day 7. Nuclei immunoreactive with BrdU were quantitated, and the index in the neointima was reported. (b) TUNEL index. Mice were subjected to femoral artery guide-wire injury followed by sacrifice on day 7. Vessels were subjected to TUNEL staining, and data are expressed as an index of TUNEL-positive nuclei in the neointima. (c and d) Activation of Erk1/2 and PKB. Mice were subjected to femoral artery guide-wire injury and sacrificed 30 min later. SDS-PAGE/Western blotting with Ab’s to phospho-Erk1/2 (p-Erk1/2) or total Erk1/2 (c) or phospho-PKB (p-PKB) or total PKB were employed. (e and f) Activation of Jak2/Stat3. Mice were subjected to femoral artery guide-wire injury and sacrificed 7 days later. SDS-PAGE/Western blotting with Ab’s to phospho-Jak2 (p-Jak2) or total Jak2 (e) or phospho-Stat3 (p-Stat3) or total Stat3 (f) were employed. (g) Transcripts for MMP12, tenascin-C, and β-actin. Mice were subjected to femoral artery guide-wire injury. On day 7, total RNA was harvested for RT-PCR using the indicated primers. (h, i, and j) Masson’s trichrome stain. Mice were subjected to femoral artery guide-wire injury and sacrificed on day 28. Sections of femoral artery were stained with Masson’s trichrome reagent (i and j), and images were analyzed to determine the area occupied by blue staining ECM (h). Scale bar: 50 μm. The above experiments employed at least eight vessels for each experimental condition, and experiments were repeated three times.