Beschreibung:
<jats:p>
The phenotypic plasticity of vascular smooth muscle cells (VSMCs) is central to growth and remodeling processes, but also contributes to the pathology of atherosclerosis, restenosis, and other cardiovascular diseases. This ability of VSMCs to reversibly differentiate and de-differentiate is incompletely understood. SUV39H1, a histone methyltransferase, specifically trimethylates Lys-9 of histone H3 (H3K9me3), resulting in epigenetic transcriptional repression. We hypothesized that SUV39H1 plays a role in VSMC phenotypic switching. Using knockdown, qPCR, western blot, chromatin immunoprecipitation (ChIP), RNA-Seq, and murine vascular injury to determine the role of SUV39H1 in VSMC plasticity. A qPCR array screen of epigenetic regulators revealed that SUV39H1 is upregulated with PDGF-induced dedifferentiation but downregulated with rapamycin-induced differentiation in hCASMCs. SUV39H1 knockdown promoted differentiation measured by increased contractile gene, protein expression, enhanced contractility, decreased migration, proliferation, and de-differentiation-associated gene expression. RNA-seq trasncriptomics confirmed changes in multiple pathways consistent with a role for SUV39H1 in promoting hCASMC dedifferentiation. Mechanistically, SUV39H1 knockdown suppressed expression of KLF4, the master transcriptional regulator of VSMC dedifferentiation, decreasing KLF4 mRNA stability and upregulating miRNA143, a known repressor of KLF4. siSUV39H1 also increased expression of KDM4a, a JMJD family lysine demethylase that targets H3K9me3. ChIP assays at contractile gene promoters showed significant decrease in the H3K9me3 mark and increase in H3K27Ac after SUV39H1 knockdown.
<jats:italic>In vivo,</jats:italic>
we noted a significant increase in SUV39H1 and H3K9me3 expression in murine carotid artery ligation induced intimal hyperplasia. We identify SUV39H1 as an epigenetic regulator of VSMC phenotype whose expression and activity increase with dedifferentiation
<jats:italic>in vitro</jats:italic>
and
<jats:italic>in vivo</jats:italic>
. PDGF promotes H3K9me3 repressive marks at contractile genes by promoting expression of SUV39H1, which also inhibits the KDM4a. Understanding the role of SUV39H1 in VSMC plasticity may reveal new therapeutic strategies for treating vascular diseases.
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