From the Key Laboratory of Cardiovascular Disease and Department of Pathophysiology (L.Y., G.Y., X.W., P.L., L.L., J.L., Z.F., W.T., X.W., H.X., M.F., Y.J., Y.L., Q.C., Y.X.) and Laboratory Center for Basic Medical Sciences (X.W.), Nanjing Medical University, Nanjing, China; and Department of Surgery, Jiangsu Jiankang Vocational University, Nanjing, China (M.F.).
Arterioscler Thromb Vasc Biol. 2015 May;35(5):1207-17. doi: 10.1161/ATVBAHA.115.305230. Epub 2015 Mar 26.
Endothelin-1 is a potent vasoconstrictor derived from vascular endothelium. Elevated endothelin-1 levels are observed in a host of cardiovascular pathologies including cardiomyopathy. The epigenetic mechanism responsible for endothelin-1 induction in these pathological processes remains elusive.
We report here that induction of endothelin-1 expression in endothelial cells by angiotensin II (Ang II) was accompanied by the accumulation of histone H3K4 trimethylation, a preeminent histone modification for transcriptional activation, on the endothelin-1 promoter. In the meantime, Ang II stimulated the expression and the occupancy of Suv, Ez, and Trithorax domain 1 (SET1), a mammalian histone H3K4 trimethyltransferase, on the endothelin-1 promoter, both in vitro and in vivo. SET1 was recruited to the endothelin-1 promoter by activating protein 1 (c-Jun/c-Fos) and synergized with activating protein 1 to activate endothelin-1 transcription in response to Ang II treatment. Knockdown of SET1 in endothelial cells blocked Ang II-induced endothelin-1 synthesis and abrogated hypertrophy of cultured cardiomyocyte. Finally, endothelial-specific depletion of SET1 in mice attenuated Ang II-induced pathological hypertrophy and cardiac fibrosis.
Our data suggest that SET1 epigenetically activates endothelin-1 transcription in endothelial cells, thereby contributing to Ang II-induced cardiac hypertrophy. As such, screening of small-molecule compound that inhibits SET1 activity will likely offer a new therapeutic solution to the treatment of cardiomyopathy.
内皮素-1 是一种源自血管内皮的强效血管收缩剂。在包括心肌病在内的多种心血管病理中，均可观察到内皮素-1 水平升高。导致这些病理过程中内皮素-1 诱导的表观遗传机制仍不清楚。
我们在此报告，血管紧张素 II（Ang II）诱导内皮细胞内皮素-1 表达伴随着组蛋白 H3K4 三甲基化的积累，这是转录激活的主要组蛋白修饰，在内皮素-1 启动子上。同时，Ang II 在体外和体内均刺激内皮素-1 启动子上 Suv、Ez 和 Trithorax 结构域 1（SET1）的表达和占据，SET1 是一种哺乳动物组蛋白 H3K4 三甲基转移酶。SET1 通过激活蛋白 1（c-Jun/c-Fos）被招募到内皮素-1 启动子上，并与激活蛋白 1 协同作用，响应 Ang II 处理激活内皮素-1 转录。内皮细胞中 SET1 的敲低阻断了 Ang II 诱导的内皮素-1 合成，并消除了培养的心肌细胞的肥大。最后，内皮细胞特异性敲除 SET1 可减轻 Ang II 诱导的病理性肥大和心脏纤维化。
我们的数据表明，SET1 在血管内皮细胞中通过表观遗传激活内皮素-1 转录，从而促进 Ang II 诱导的心肌肥大。因此，筛选抑制 SET1 活性的小分子化合物可能为治疗心肌病提供新的治疗解决方案。
