| First Author | Lino Cardenas CL | Year | 2018 |
| Journal | JCI Insight | Volume | 3 |
| Issue | 5 | PubMed ID | 29515022 |
| Mgi Jnum | J:299129 | Mgi Id | MGI:6490142 |
| Doi | 10.1172/jci.insight.97493 | Citation | Lino Cardenas CL, et al. (2018) Inhibition of the methyltranferase EZH2 improves aortic performance in experimental thoracic aortic aneurysm. JCI Insight 3(5) |
| abstractText | 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 SM22alpha was inversely correlated with aneurysm size. SM22alpha-deficient mice demonstrated pregnancy-induced aortic dissection, and SM22alpha deficiency worsened aortic aneurysm in Fbn1C1039G/+ (Marfan) mice, validating this gene product as a TAA effector. We found that repression of SM22alpha was enforced by increased activity of the methyltransferase EZH2. TGF-beta effectors such as SMAD3 were excluded from binding SM22alpha-encoding chromatin (TAGLN) in TAA samples, while treatment with the EZH2 inhibitor GSK343 improved cytoskeletal architecture and restored SM22alpha expression. Finally, inhibition of EZH2 improved aortic performance in Fbn1C1039G/+ mice, in association with restoration of contractile protein expression (including SM22alpha). 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. |
