开发一个定量系统药理学模型,以询问心力衰竭中的线粒体代谢
Lyndsey F Meyer1, Neda Nourabadi2, Cynthia J Musante1
1Pfizer Research and Development, Cambridge, MA, USA.
bioRxiv : the preprint server for biology
|July 17, 2025
概括
心力衰竭 (HF) 改变心脏代谢,减少运动能力. 定量系统药理模型显示,酸盐脱酶 (PDH) 活性是HF中基质选择和能量生产的关键.
科学领域:
- 心血管新陈代谢的发生.
- 线粒体功能的功能
- 系统药理学系统药理学
背景情况:
- 心力衰竭 (HF) 的特点是心脏能量代谢受损,包括减少ATP水解和从脂肪酸转向碳水化合物利用.
- 这些代谢变化有助于降低HF患者的运动耐受性,但潜在的机制仍然不清楚.
研究的目的:
- 开发和利用线粒体新陈代谢的定量系统药理学 (QSP) 模型,以研究将代谢功能障碍与高频心脏功率输出减少联系起来的机制.
- 了解线粒体功能的变化和心脏能量如何影响高频运动能力.
主要方法:
- 在氧化酸化,三碳酸循环和β-氧化等化模型中综合发表.
- 将模型扩展为更新的酸盐脱酶 (PDH) 表示,以分析基质选择.
- 模拟代谢功能障碍,如PDH活性降低或线粒体体积改变,以评估对能量生物标记物的影响,如脂蛋白-ATP比率 (PCr/ATP).
主要成果:
- 在健康和模拟HF条件下,QSP模型准确地预测了燃料选择的变化.
- 确定PDH活性对于基质依赖的代谢切换至关重要,由涉及NAD,NADH,ATP,ADP,CoASH,Acetyl-CoA和pyruvate的反机制调节.
- 模拟表明,较高的马洛尼尔-CoA可能有助于在一些HF患者的运动期间观察到的PCr/ATP比率降低.
结论:
- 开发的QSP模型提供了对HF中线粒体代谢的复杂相互作用的见解.
- PDH活动在调节心脏基质利用和能量生产方面发挥着关键作用,调节失调有助于HF病理生理学.
- 升高的马洛尼尔-CoA是高频运动期间心脏能量受损的潜在因素.
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