Joshi Divyesh, Chakraborty Raja, Bhogale Tejas, Furtado Jessica, Deng Hanqiang, Traylor James G, Orr Anthony Wayne, Martin Kathleen A, Schwartz Martin A
Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT 06511, USA.
Department of Cellular and Molecular Physiology, Yale University, New Haven, CT 06520, USA.
bioRxiv. 2024 Dec 2:2024.12.02.626505. doi: 10.1101/2024.12.02.626505.
Atherosclerotic cardiovascular disease (ASCVD), the leading cause of mortality worldwide, is driven by endothelial cell inflammatory activation and counter-balanced by anti-inflammatory transcription factors Klf2 and Klf4 (Klf2/4). Understanding vascular endothelial inflammation to develop effective treatments is thus essential. Here, we identify, Polycomb Repressive Complex (PRC) 2, which blocks gene transcription by trimethylating histone3 Lysine27 in gene promoter/enhancers, as a potent, therapeutically targetable determinant of vascular inflammation and ASCVD progression. Bioinformatics identified PRC2 as a direct suppressor of Klf2/4 transcription. Klf2/4 transcription requires Notch signaling, which reverses PRC2 modification of Klf2/4 promoter/enhancers. PRC2 activity is elevated in human ASCVD endothelium. Treating mice with established ASCVD with tazemetostat, an FDA approved pharmacological inhibitor of PRC2, slowed plaque progression by 50% and drastically improved markers of plaque stability. This study elucidates a fundamental mechanism of vascular inflammation, thus identifying a potential method for treating ASCVD and possibly other vascular inflammatory diseases.
动脉粥样硬化性心血管疾病（ASCVD）是全球范围内的主要死亡原因，由内皮细胞炎症激活驱动，并由抗炎转录因子Klf2和Klf4（Klf2/4）进行平衡。因此，了解血管内皮炎症以开发有效的治疗方法至关重要。在这里，我们确定了多梳抑制复合物（PRC）2，它通过在基因启动子/增强子中对组蛋白3赖氨酸27进行三甲基化来阻断基因转录，是血管炎症和ASCVD进展的一个强有力的、可治疗靶向的决定因素。生物信息学确定PRC2是Klf2/4转录的直接抑制因子。Klf2/4转录需要Notch信号传导，该信号传导可逆转PRC2对Klf2/4启动子/增强子的修饰。PRC2活性在人类ASCVD内皮细胞中升高。用他泽司他（一种FDA批准的PRC2药理抑制剂）治疗患有已确诊ASCVD的小鼠，可使斑块进展减缓50%，并显著改善斑块稳定性标志物。这项研究阐明了血管炎症的基本机制，从而确定了一种治疗ASCVD以及可能其他血管炎性疾病的潜在方法。
