Formin mDia1 Mediates Vascular Remodeling via Integration of Oxidative and Signal Transduction Pathways

Abstract

Rationale The mammalian Diaphanous-related formin, mDia1, governs microtubule and microfilament dynamics while functioning as an effector for Rho small GTP-binding proteins during key cellular processes such as adhesion, cytokinesis, cell polarity and morphogenesis. The cytoplasmic domain of the receptor for advanced glycation endproducts (RAGE) binds to the formin homology 1 (FH1) domain of mDia1; mDia1 is required for RAGE ligand-induced cellular migration in transformed cells. Objective As a key mechanism in vascular remodeling is the induction of smooth muscle cell migration, we tested the role of mDia1 in this process. Methods and Results We report that endothelial denudation injury to the murine femoral artery significantly upregulates mDia1 mRNA transcripts and protein in the injured vessel, particularly in vascular smooth muscle cells within the expanding neointima. Loss of mDia1 expression significantly reduces pathological neointimal expansion consequent to injury. In primary murine aortic smooth muscle cells, mDia1 is required for RAGE ligand-induced membrane translocation of c-Src, which leads to Rac1 activation, redox phosphorylation of AKT/GSK3β and consequent smooth muscle cell migration. Conclusions We conclude that mDia1 integrates oxidative and signal transduction pathways triggered, at least in part by RAGE ligands, therefore regulates pathological neointimal expansion.

Signaling of Serum Amyloid A Through Receptor for Advanced Glycation End Products as a Possible Mechanism for Uremia-Related Atherosclerosis

“…Furthermore, we previously showed that the oxidative stress was a key mechanism by which RAGE mediated its effects. 25,34 This study supports the view that RAGE-mediated oxidative stress is important for the regulation of VSMC migration, thereby highlighting the link between RAGE and oxidative stress. Our results suggest a possible role for the SAA-RAGE interaction in the pathophysiology of uremic atherosclerosis.…”

KCa3.1 channels mediate the increase of cell migration and proliferation by advanced glycation endproducts in cultured rat vascular smooth muscle cells

“…The phosphorylation of PI3K is also essential for RAGE ligand-induced VSMC migration and proliferation. 24 In the present study, we found that specific signal inhibitors, PD98059 and U0126 for ERK1/2, SB203580 and SB202190 for P38-MAPK, and LY294002 and wortmannin for PI3K/Akt, markedly decreased AGEsinduced upregulation of K Ca 3.1 channel expression in rat VSMCs, indicating that activation of these cellular signaling pathways mediate the AGEs-induced increase of K Ca 3.1 channels. This is supported by previous reports, in which ERK induces an increase of proliferative gene expression, eg, the AP-1 family member c-fos, [25][26][27] and the increased production of c-fos leads to induction of K Ca 3.1 expression through AP-1 promoter elements.…”

RAGE binds preamyloid IAPP intermediates and mediates pancreatic β cell proteotoxicity

“…We also expected that sRAGE would compete with cellsurface RAGE for h-IAPP binding, as it targets toxic LP intermediates and is a competitive inhibitor of ligand binding to cell membrane-bound RAGE. To test this, we used INS-1 β cells and primary murine aortic smooth muscle cells (SMCs) as model systems (50,52). We prepared h-IAPP LP intermediates, a 1:1 molar mixture of h-IAPP/sRAGE, and multiple controls including sRAGE, r-IAPP, and buffer-only solutions.…”