由SETD2进行的染色体重新连接驱动心脏代谢HFpEF中的脂毒性损伤
Sarah Costantino1, Shafeeq A Mohammed1, Samuele Ambrosini1
1Department of Cardiology, Center for Translational and Experimental Cardiology, University Hospital Zurich (S.C., S.A.M., S.A., M.T., A.M., E.G., J.X., O.D., F.R., F.P.), University of Zurich, Switzerland.
Circulation research
|April 11, 2025
概括
准SETD2,这是一种参与基因素修饰的酶,可以防止心脏代谢性心力衰竭中的脂毒性损伤,并保留喷射分数 (cHFpEF). 这项研究发现cHFpEF心脏中的SETD2升调,导致脂质积累和功能障碍.
科学领域:
- 心脏病学 心脏病学
- 分子生物学分子生物学
- 表观遗传学 在表观遗传学中,表观遗传学是指表观遗传学.
背景情况:
- 心脏代谢性心力衰竭与保存的喷射分数 (cHFpEF) 是一种普遍且致命的疾病.
- 在cHFpEF病原发生过程中,基因组甲基化,特别是由SETD2诱导的H3K36me3的作用尚不清楚.
- SETD2是一种基因甲基转移酶,涉及基因表达调节.
研究的目的:
- 调查SETD2在cHFpEF发展中的作用.
- 探索针对cHFpEF中的SETD2的治疗潜力.
主要方法:
- 利用染色体免疫沉降测序和RNA测序来分析与H3k36me3相关的转录调节.
- 通过高脂肪饮食和L-NAME诱导产生心肌细胞特异性SETD2淘汰赛小鼠 (c-SETD2-/-) 和诱导cHFpEF.
- 评估心脏功能,运动耐受性,并在临床前模型和患者衍生细胞中使用SETD2抑制剂 (EZM0414).
主要成果:
- 在cHFpEF心脏中,SETD2和H3k36me3被上调,富含SREBF1促进剂,导致SREBP1上调和脂毒性.
- 特定于心肌细胞的SETD2删除阻止了cHFpEF的发展,通过重新连接脂质代谢和恢复自,改善了心脏功能和运动耐受性.
- 用EZM0414对SETD2的药理抑制模仿了体内和体外SETD2删除的保护作用,降低了心肌细胞硬度.
结论:
- 通过通过SREBP1激活促进脂毒性损伤,SETD2在cHFpEF病原发生中发挥着关键作用.
- 用EZM0414等抑制剂向SETD2代表了对cHFpEF的有希望的治疗策略.
- 需要进一步研究SETD2介导的心力衰竭中的表观遗传调节.
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