Splicing of Histone Deacetylase 7 Modulates Smooth Muscle Cell Proliferation and Neointima Formation Through Nuclear β-Catenin Translocation

Abstract

Objective-Vascular smooth muscle cell (SMC) proliferation has an indispensable role in the pathogenesis of vascular disease, but the mechanism is not fully elucidated. The epigenetic enzyme histone deacetylase 7 (HDAC7) is involved in endothelial homeostasis and SMC differentiation and could have a role in SMC proliferation. In this study, we sought to examine the effect of 2 HDAC7 isoforms on SMC proliferation and neointima formation. Methods and Results-We demonstrated that overexpression of unspliced HDAC7 (HDAC7u) could suppress SMC proliferation through downregulation of cyclin D1 and cell cycle arrest, whereas spliced HDAC7 (HDAC7s) could not. Small interfering RNA (siRNA)-mediated knockdown of HDAC7 increased SMC proliferation and induced nuclear translocation of ␤-catenin. Additional experiments showed that only HDAC7u could bind to ␤-catenin and retain it in the cytoplasm. Reporter gene assay and reverse transcription polymerase chain reaction revealed a reduction of ␤-catenin activity in cells overexpressing HDAC7u but not HDAC7s. Deletion studies indicated that the C-terminal region of HDAC7u is responsible for the interaction with ␤-catenin. However, the addition of amino acids to the N terminus of HDAC7u disrupted the binding, further strengthening our hypothesis that HDAC7s does not interact with ␤-catenin. The growth factor platelet-derived growth factor-BB increased the splicing of HDAC7 while simultaneously decreasing the expression of HDAC7u. Importantly, in an animal model of femoral artery wire injury, we demonstrated that knockdown of HDAC7 by siRNA aggravates neointima formation in comparison with control siRNA. Conclusion-Our findings demonstrate that splicing of HDAC7 modulates SMC proliferation and neointima formation through ␤-catenin nuclear translocation, which provides a potential therapeutic target in vascular disease. Key Words: HDAC Ⅲ beta catenin Ⅲ mouse model Ⅲ neointima Ⅲ smooth muscle V ascular smooth muscle cells (SMCs) are essential cellular components of blood vessels and play a pivotal role in the pathogenesis of arteriosclerosis. After vascular injury by risk factors, 1 various growth factors (eg, plateletderived growth factor [PDGF], transforming growth factor-␤) and cytokines (eg, interferon-␥) are released by different cell types (eg, endothelial cells, platelets, and monocytes). 2 This significantly promotes SMC proliferation that is indispensable to the formation of in-stent restenosis, transplant arteriosclerosis, and vein graft failure. 3 PDGF-BB release closely correlates with arteriosclerosis, probably because of its effects on SMC proliferation and migration. PDGF-BB binds and activates its receptor, PDGF receptor-␤. This initiates the activation of several pathways, including the extracellular signal-regulated kinase and phosphatidylinositol 3-kinase pathways. 4 However, the detailed mechanisms of the signaling pathways involved in SMC proliferation remain to be fully elucidated.Histone deacetylases (HDACs) are a family of enzymes that remove acetyl groups fro...

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“…HDAC7 siRNA intensified neointima formation, highlighting also the HDAC7 involvement during the pathogenesis of arteriosclerosis [32].…”

Inhibition of Patched-1 Prevents Injury-Induced Neointimal Hyperplasia

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“…Additionally, HDAC4 has been suggested to control neointima hyperplasia by promoting the activation of p38 mitogen-activated protein kinase/heat shock protein 27 signaling and inducing VSMC proliferation and migration 74 . In contrast, HDAC7 (unspliced isoform) was shown to suppress VSMC proliferation and neointima formation by preventing β-catenin nuclear translocation and activity 75 . Class I/II HDAC inhibition increased neointimal thickening in a murine model of post-angioplasty restenosis 76 , while class IIa HDAC inhibition prevented neointimal hyperplasia in a murine carotid ligation model 74 .…”