HDAC9 complex inhibition improves smooth muscle–dependent stenotic vascular disease

Christian L. Lino Cardenas, Chase W. Kessinger, Elizabeth Chou, Brian Ghoshhajra, Ashish S. Yeri, Saumya Das, Neal L. Weintraub, Rajeev Malhotra, Farouc A. Jaffer, Mark E. Lindsay

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Patients with heterozygous missense mutations in the ACTA2 or MYH11 gene are known to exhibit thoracic aortic aneurysm and a risk of early-onset aortic dissection. However, less common phenotypes involving arterial obstruction are also observed, including coronary and cerebrovascular stenotic disease. Herein we implicate the HDAC9 complex in transcriptional silencing of contractile protein–associated genes, known to undergo downregulation in stenotic lesions. Furthermore, neointimal formation was inhibited in HDAC9-or MALAT1-deficient mice with preservation of contractile protein expression. Pharmacologic targeting of the HDAC9 complex through either MALAT1 antisense oligonucleotides or inhibition of the methyltransferase EZH2 (catalytic mediator recruited by the HDAC9 complex) reduced neointimal formation. In conclusion, we report the implication of the HDAC9 complex in stenotic disease and demonstrate that pharmacologic therapy targeting epigenetic complexes can ameliorate arterial obstruction in an experimental system.

Original languageEnglish (US)
Article numberY
JournalJCI Insight
Volume4
Issue number2
DOIs
StatePublished - Jan 24 2019

ASJC Scopus subject areas

  • Medicine(all)

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    Lino Cardenas, C. L., Kessinger, C. W., Chou, E., Ghoshhajra, B., Yeri, A. S., Das, S., Weintraub, N. L., Malhotra, R., Jaffer, F. A., & Lindsay, M. E. (2019). HDAC9 complex inhibition improves smooth muscle–dependent stenotic vascular disease. JCI Insight, 4(2), [Y]. https://doi.org/10.1172/jci.insight.124706