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Inhibition of the methyltranferase EZH2 improves aortic performance in experimental thoracic aortic aneurysm
Christian L. Lino Cardenas, … , Farouc A. Jaffer, Mark E. Lindsay
Christian L. Lino Cardenas, … , Farouc A. Jaffer, Mark E. Lindsay
Published March 8, 2018
Citation Information: JCI Insight. 2018;3(5):e97493. https://doi.org/10.1172/jci.insight.97493.
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Research Article Cardiology Cell biology

Inhibition of the methyltranferase EZH2 improves aortic performance in experimental thoracic aortic aneurysm

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Abstract

Loss-of-function mutations in genes encoding contractile proteins have been observed in thoracic aortic aneurysms (TAA). To gain insight into the contribution of contractile protein deficiency in the pathogenesis of TAA, we examined human aneurysm samples. We found multiple contractile gene products deficient in TAA samples, and in particular, expression of SM22α was inversely correlated with aneurysm size. SM22α-deficient mice demonstrated pregnancy-induced aortic dissection, and SM22α deficiency worsened aortic aneurysm in Fbn1C1039G/+ (Marfan) mice, validating this gene product as a TAA effector. We found that repression of SM22α was enforced by increased activity of the methyltransferase EZH2. TGF-β effectors such as SMAD3 were excluded from binding SM22α-encoding chromatin (TAGLN) in TAA samples, while treatment with the EZH2 inhibitor GSK343 improved cytoskeletal architecture and restored SM22α expression. Finally, inhibition of EZH2 improved aortic performance in Fbn1C1039G/+ mice, in association with restoration of contractile protein expression (including SM22α). Together, these data inform our understanding of contractile protein deficiency in TAA and support the pursuit of chromatin modifying factors as therapeutic targets in aortic disease.

Authors

Christian L. Lino Cardenas, Chase W. Kessinger, Carolyn MacDonald, Arminder S. Jassar, Eric M. Isselbacher, Farouc A. Jaffer, Mark E. Lindsay

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Figure 1

Decrement of members of the VSMC contractile apparatus in patients with TAA.

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Decrement of members of the VSMC contractile apparatus in patients with ...
(A) Expression pattern of VSMC phenotypic markers in human aortic tissue from control (n = 13) and TAAD (n = 30) donors. Loss of TAGLN (SM22α) transcript were more significant in patients who have experienced dissection (TAA FC = 0.55 vs TAAD FC = 0.12). (B) Immunoblotting analysis of SM22α protein in human aortic tissue from control (n = 7) and TAAD (n = 9) donors. (C) Anatomical reconstruction of patient images and immunofluorescence staining of contractile proteins of human aortas from control, TAA, and TAAD samples (top row). Verhoeff-Van Gieson stain (VVG) staining of aortic samples from patients demonstrates elastin fragmentation. Scale bar: 150 μm (second row). Immunofluorescence from aortic samples showing SM22α (magenta), calponin (Cnn) (green), DAPI (blue), vinculin (red), smoothelin (green), and DAPI (blue). Scale bar: 50 μm, inset zoom 3-fold magnification. (D) Representative photomicrographs of latex-injected WT and Fbn1C1039G/+ mouse hearts and ascending aortas. Red arrows indicate the ascending portion of the aorta. Aortic elastin fibers were stained with Verhoeff-Van Gieson stain (VVG), and immunofluorescence of DAPI (blue), F-actin (green), and Sm22α (magenta). Scale bar: 50 μm. (E) qPCR analysis of Tagln (Sm22α) transcript in aortic tissue and plasma from WT (n = 7) and Fbn1C1039G/+ (n = 7) 6-month-old mice. (F) Correlation of Tagln (Sm22α) tissue expression with aortic dimensions in Fbn1C1039G/+ aortas (n = 7) (least squares method used for curve fit). (G) Immunofluorescence staining of contractile proteins in aortic VMSC treated with siCtrl or siSM22α. Scale bar: 10 μm, zoom 3-fold magnification. (H) Immunoblotting analysis of SM22α inhibition and loss of its binding partner Cnn in aortic VMSC. Quantitation versus β-actin shown below. (I) siSM22α treatment of healthy VSMCs induce MMP activity as assessed by in vitro gelatin zymography. (*P < 0.05, **P < 0.01, ***P < 0.001, student’s t test, 2 tailed). FC, fold change; TAA, Thoracic aortic aneurysm; TAAD, Thoracic aortic aneurysm and dissection; Ctrl, control; SMTN, smoothelin; VCL, vinculin.

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