Abstract 9896: Reduction of Endoplasmic Reticulum Stress Prevent Neointima Formation After Vascular Injury

Abstract

[Background] Restenosis after percutaneous coronary intervention is still a major obstacle in treatment of coronary artery disease. The endoplasmic reticulum (ER) stress and inappropriate adaptation through the unfolded protein response (UPR) is a predominant feature in pathological processes in several types of tissues. However, little is known about the link between ER stress and vascular diseases. In this study, we investigated involvement of ER stress in neointima hyperplasia after vascular injury. [Methods & Results] The femoral artery of 7-8-week male mice was subjected to wire-induced vascular injury. After 4 weeks, immunohistological analysis showed that ER stress markers, including phosphorylation of eukaryotic initiation factor 2α (eIF2α) and inositol-requiring enzyme-1 (IRE1), protein disulfide isomerase (PDI), glucose-regulated protein 94 (GRP94), and C/EBP homologous protein (CHOP) were up-regulated in hyperplastic neointima in injured regions. Treatment with 4-phenylbutyrate (PBA) and tauroursodeoxycholic acid (TUDCA), chemical chaperones, significantly reduced intima/media ratio by 46.6% and 70.9%, respectively, compared with the control. In the second series of experiments, the involvement of ER stress in cell proliferation was examined in human coronary artery smooth muscle cell (CASMC). Stimulation of CASMCs with platelet-derived growth factor (PDGF) led to activation of the UPR, which was indicated by a phosphorylation of IRE1 and eIF2α and an induction of GRP78 and PDI proteins, and the UPR was accompanied by phosphorylation of extracellular signal-regulated kinase (ERK). Elevation of mRNA levels of GRP94, GRP78, PDI, and spliced form of X-box binding protein 1 after PDGF treatment was confirmed by quantitative RT-PCR. PBA significantly suppressed PDGF-induced elevation of protein and mRNA levels of the ER stress markers and inhibited proliferation of CASMC by 62.9%. [Conclusions] Our findings suggest that ER stress plays a significant role of neointima hyperplasia after vascular injury and that reduction of ER stress might be a novel strategy against post-angioplasty restenosis.