Abstract 357: The Role of X-Box Binding Protein 1 Splicing in Smooth Muscle Cell Proliferation and Neointima Formation

Abstract

Rationale: Smooth muscle cell (SMC) proliferation plays an important role in neointima formation in response to vascular injury. However, the underlying mechanism is still not well understood. As one of the key transducer in endoplasmic reticulum stress response, the X-box binding protein 1 (XBP1) has been demonstrated to contribute to endothelial cell proliferation, autophagic response and apoptosis, but less is known about its role in SMC growth. Methods and Results: In this study, we intend to study the role of XBP1 in SMC proliferation and its contribution to neointima formation in response to vascular injury. Platelet derived growth factor (PDGF) induced XBP1 splicing in SMCs via the interaction between PDGF receptor and inositol requiring enzyme 1 alpha (IRE1α). Transient over-expression of the spliced XBP1 (XBP1s) increased SMC proliferation, while knockdown of XBP1 or IRE1α abolished PDGF-induced SMC proliferation. XBP1s down-regulated calponin H1 gene expression at mRNA level through microRNAs targeting the 3’-terminal untranslated region. Reconstitution of calponin H1 via adenoviral transfer could ablate XBP1s-induced SMC proliferation. Proteomics analysis of secreted proteins revealed that over-expression of XBP1s in SMCs decreased the secretion of transforming growth factor β family. Addition of exogenous TGFβ3 abolished XBP1s-induced calponin H1 suppression and SMC proliferation. High levels of TGFβ3 and calponin H1 were detected in SMCs isolated from SM22-Cre/XBP1loxP mice. These SMCs showed retardation in proliferation. Importantly, in the femoral artery injury model, XBP1 deficiency in SMCs prevented the neointima formation. Conclusion: XBP1 splicing plays an important role in SMC proliferation via regulating calponin H1 expression. Targeting XBP1 splicing in SMC may provide a novel therapeutic strategy to intervene neointima formation.