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 β-catenin. Additional experiments showed that only HDAC7u could bind to β-catenin and retain it in the cytoplasm. Reporter gene assay and reverse transcription polymerase chain reaction revealed a reduction of β-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 β-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 β-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 β-catenin nuclear translocation, which provides a potential therapeutic target in vascular disease.

• Authors: Boda Zhou, Andriana Margariti, Lingfang Zeng, Ouassila Habi, Qingzhong Xiao, Daniel Martin, Gang Wang, Yanhua Hu, Xian Wang, Qingbo Xu
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 31 Issue 11 Pg. 2676-84 (Nov 2011) ISSN: 1524-4636 [Electronic] United States
• PMID: 21836063 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Platelet-Derived Growth Factor
• Proto-Oncogene Proteins c-sis
• RNA, Small Interfering
• beta Catenin
• Becaplermin
• Hdac7 protein, mouse
• Histone Deacetylases

Topics

• Alternative Splicing (drug effects, physiology)
• Animals
• Aorta (cytology, metabolism)
• Becaplermin
• Cell Nucleus (metabolism)
• Cell Proliferation
• Cells, Cultured
• Cytoplasm (metabolism)
• Femoral Artery (injuries, metabolism)
• Histone Deacetylases (drug effects, genetics, metabolism)
• Humans
• Mice
• Models, Animal
• Muscle, Smooth, Vascular (cytology, metabolism)
• Neointima (metabolism)
• Platelet-Derived Growth Factor (pharmacology)
• Proto-Oncogene Proteins c-sis
• RNA, Small Interfering (pharmacology)
• beta Catenin (metabolism)