Left ventricular hypertrophy (LVH) is a major risk factor for cardiovascular morbidity and mortality. Pathological LVH engages transcriptional programs including reactivation of canonical fetal genes and those inducing fibrosis. Histone lysine demethylases (KDMs) are emerging regulators of transcriptional reprogramming in cancer, though their potential role in abnormal heart growth and fibrosis remains little understood. Here, we investigate gain and loss of function of an H3K9me2 specific demethylase, Kdm3a, and show it promotes LVH and fibrosis in response to pressure-overload. Cardiomyocyte KDM3A activates Timp1 transcription with pro-fibrotic activity. By contrast, a pan-KDM inhibitor, JIB-04, suppresses pressure overload-induced LVH and fibrosis. JIB-04 inhibits KDM3A and suppresses the transcription of fibrotic genes that overlap with genes downregulated in Kdm3a-KO mice versus WT controls. Our study provides genetic and biochemical evidence for a pro-hypertrophic function of KDM3A and proof-of principle for pharmacological targeting of KDMs as an effective strategy to counter LVH and pathological fibrosis.

中文翻译：

---

组蛋白赖氨酸二甲基去甲基化酶 KDM3A 控制病理性心脏肥大和纤维化。

左心室肥厚 (LVH) 是心血管疾病发病率和死亡率的主要危险因素。病理性 LVH 参与转录程序，包括经典胎儿基因的重新激活和那些诱导纤维化的基因。组蛋白赖氨酸去甲基化酶 (KDM) 是癌症中转录重编程的新兴调节因子，尽管它们在心脏异常生长和纤维化中的潜在作用仍知之甚少。在这里，我们研究了 H3K9me2 特异性去甲基化酶 Kdm3a 的功能获得和丧失，并表明它促进了 LVH 和纤维化以响应压力过载。心肌细胞 KDM3A 激活具有促纤维化活性的 Timp1 转录。相比之下，泛 KDM 抑制剂 JIB-04 可抑制压力超负荷诱导的 LVH 和纤维化。JIB-04 抑制 KDM3A 并抑制与 Kdm3a-KO 小鼠与 WT 对照中下调的基因重叠的纤维化基因的转录。我们的研究为 KDM3A 的促肥大功能提供了遗传和生化证据，并为 KDM 的药理学靶向作为对抗 LVH 和病理性纤维化的有效策略提供了原理证明。