依赖ATP的酸酶通过心脏的代谢重塑驱动左心室功能障碍
bioRxiv : the preprint server for biology
|July 1, 2024
概括
依赖ATP的酸酶 (ACL) 酶对心脏功能和脂质合成至关重要. 失去ACL会引发代谢转变,包括增加葡萄糖氧化,以维持心脏功能.
科学领域:
- 心血管新陈代谢的发生.
- 瘤代谢的代谢过程
- 分子心脏病学分子心脏病学
背景情况:
- 代谢重塑是心力衰竭的一个关键特征.
- 与癌症相关的代谢压力提高了依赖ATP的酸酶 (ACL),影响了基因素乙化和心脏适应.
- 在心脏结构和功能变化中,ACL驱动的脂质合成的作用尚未完全理解.
研究的目的:
- 研究ACL在心脏代谢适应和功能中的作用.
- 阐明ACL缺乏影响心脏新陈代谢的机制.
- 为了确定与ACL抑制相关的心脏中的代谢脆弱性.
主要方法:
- 分析了来自健康捐赠者和患有多变性心肌病的患者的人类心脏组织.
- 使用CRISPR/Cas9基因编辑来使小鼠心肌细胞中的ACL失活.
- 在体内PET成像和体外稳定同位素追踪量化了代谢流量.
- 采用了多组学 (RNA-seq,代谢学,蛋白学) 和计算建模 (CardioNet).
主要成果:
- 在小鼠中,ACL支持心脏收缩功能,基因素乙化和脂质调节.
- 缺少ACL导致葡萄糖氧化增加和脂肪酸氧化维持.
- 从线粒体到细胞质中的酸盐流量减少,突出显示了它在还原代谢中的作用.
- 失去ACL会通过异酸脱酶1 (IDH1) 诱导补偿流.
结论:
- 心脏代谢补偿ACL损失后抑制的酸盐代谢.
- 这项研究揭示了对心脏代谢适应的机制性见解.
- 发现了与心脏中ACL缺陷相关的代谢漏洞.
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