The Histone Deacetylase 9 Stroke-Risk Variant Promotes Apoptosis and Inflammation in a Human iPSC-Derived Smooth Muscle Cells Model.


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Authors
Granata, Alessandra 
Kasioulis, Ioannis 
Serrano, Felipe 
Cooper, James D 
Traylor, Matthew 
Abstract

A common variant in the Histone Deacetylase 9 (HDAC9) gene is the strongest genetic risk for large-vessel stroke, and HDAC9 offers a novel target for therapeutic modulation. However, the mechanisms linking the HDAC9 variant with increased stroke risk is still unclear due to the lack of relevant models to study the underlying molecular mechanisms. We generated vascular smooth muscle cells using human induced pluripotent stem cells with the HDAC9 stroke risk variant to assess HDAC9-mediated phenotypic changes in a relevant cells model and test the efficacy of HDAC inhibitors for potential therapeutic strategies. Our human induced pluripotent stem cells derived vascular smooth muscle cells show enhanced HDAC9 expression and allow us to assess HDAC9-mediated effects on promoting smooth muscle cell dysfunction, including proliferation, migration, apoptosis and response to inflammation. These phenotypes could be reverted by treatment with HDAC inhibitors, including sodium valproate and small molecules inhibitors. By demonstrating the relevance of the model and the efficacy of HDAC inhibitors, our model provides a robust phenotypic screening platform, which could be applied to other stroke-associated genetic variants.

Description
Keywords
HDAC9, human induced pluripotent stem (hiPS) cells, ischemic stroke, risk variant, smooth muscle cells
Journal Title
Front Cardiovasc Med
Conference Name
Journal ISSN
2297-055X
2297-055X
Volume Title
9
Publisher
Frontiers Media SA
Sponsorship
British Heart Foundation (RG/17/5/32936)
British Heart Foundation (FS/18/46/33663)
National Institute for Health and Care Research (IS-BRC-1215-20014)
Medical Research Council (MC_PC_17230)
British Heart Foundation (None)
British Heart Foundation (PG/18/80/34109)