JCI Insight. 2020 Jul 23;5(14):137127. doi: 10.1172/jci.insight.137127.
Tissue regeneration capacity declines with aging in association with heightened oxidative stress. Expression of the oxidant-generating enzyme, NADPH oxidase 4 (Nox4), is elevated in aged mice with diminished capacity for fibrosis resolution. Bromodomain-containing protein 4 (Brd4) is a member of the bromodomain and extraterminal (BET) family of proteins that function as epigenetic "readers" of acetylated lysine groups on histones. In this study, we explored the role of Brd4 and its interaction with the p300 acetyltransferase in the regulation of Nox4 and the in vivo efficacy of a BET inhibitor to reverse established age-associated lung fibrosis. BET inhibition interferes with the association of Brd4, p300, and acetylated histone H4K16 with the Nox4 promoter in lung fibroblasts stimulated with the profibrotic cytokine, TGF-β1. A number of BET inhibitors, including I-BET-762, JQ1, and OTX015, downregulate Nox4 gene expression and activity. Aged mice with established and persistent lung fibrosis recover capacity for fibrosis resolution with OTX015 treatment. This study implicates epigenetic regulation of Nox4 by Brd4 and p300 and supports BET/Brd4 inhibition as an effective strategy for the treatment of age-related fibrotic lung disease.
随着年龄的增长，组织再生能力会下降，同时氧化应激水平也会升高。在纤维化消退能力减弱的老年小鼠中，氧化应激生成酶 NADPH 氧化酶 4（Nox4）的表达水平升高。溴结构域蛋白 4（Brd4）是溴域和末端（BET）蛋白家族的成员，作为组蛋白上乙酰化赖氨酸组的表观遗传“读取器”发挥作用。在这项研究中，我们探讨了 Brd4 及其与 p300 乙酰转移酶的相互作用在 Nox4 调节中的作用，以及 BET 抑制剂逆转已建立的与年龄相关的肺纤维化的体内疗效。BET 抑制干扰了在 TGF-β1 刺激的肺成纤维细胞中，Brd4、p300 和乙酰化组蛋白 H4K16 与 Nox4 启动子的结合。许多 BET 抑制剂，包括 I-BET-762、JQ1 和 OTX015，下调 Nox4 基因表达和活性。用 OTX015 治疗已建立和持续存在的肺纤维化的老年小鼠恢复了纤维化消退的能力。这项研究表明，Brd4 和 p300 通过表观遗传调控 Nox4，并支持 BET/Brd4 抑制作为治疗与年龄相关的纤维性肺疾病的有效策略。
