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
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
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Research Article Cardiology

HDAC9 complex inhibition improves smooth muscle–dependent stenotic vascular disease

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.

Authors

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

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Figure 2

Experimental model of arterial stenosis induces Hdac9-Brg1-Malat1 complex formation.

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Experimental model of arterial stenosis induces Hdac9-Brg1-Malat1 comple...
(A) Histological and immunofluorescence analysis of ligated and unligated carotids demonstrates neointimal formation and lumen obstruction (n = 2 male and 2 female). Ligated carotids show significant reduction in Acta2 (α-Sma, red), Sm22α (green), and increased expression of Mmp9 (orange). Significance was calculated using an unpaired t test (2-tailed, vs. unligated carotid). The red asterisk indicates the most downregulated gene in ligated carotid samples when compared with the contralateral unligated carotid. (B) Heatmap of contractile and synthetic SMC markers from ligated carotids (n = 3 male and 3 female) versus unligated carotids (n = 3 male and 3 female) of wild-type mice. (C) RT-qPCR analysis demonstrates upregulation of Hdac9 and Malat1 mRNAs in ligated carotids of wild-type mice. Significance was calculated using an unpaired t test (2-tailed, vs. unligated carotid). (D) Immunofluorescence (Hdac9 and Brg1) and in situ hybridization (Malat1) staining of ligated carotid localizes robust expression to the newly formed neointima. (E) 3D sequential immunofluorescence and in situ hybridization microscopy of ligated carotids show colocalization of Hdac9 (green), Brg1 (yellow), and Malat1 (red) in neointimal cells. Global Pearson’s colocalization (GPC) of spatial overlap between Malat1-Hdac9 and Malat1-Brg1 is shown. Scale bars: 50 μm.