从细胞因子及能量代谢角度研究慢性心力衰竭治疗的新靶点及干预策略2015心血管药理刘培庆课件.ppt

* 线粒体结构改变（Improer organization）：肿胀、嵴膜增厚、嵴皱减少、嵴膜间融合 HF 时心肌能量代谢的底物发生改变，由优先利用FA 变为优先利用葡萄糖作为能量代谢的底物。尽管葡萄糖代替FA 氧化，比较消耗每个氧原子产生的ATP 量，有轻微的节约效应，但综上所述，FA 氧化减少并不能完全被葡萄糖氧化增强所代偿，衰竭心肌ATP 再生率全面减少，心肌ATP含量减少，线粒体功能障碍。心肌存在着进行性能量衰竭，最终导致心脏功能的降低。 * * (Jennifer G. Duncan and Brian N. Finck. PPAR Research, 2008. Review Article The PPARα-PGC-1α Axis Controls Cardiac Energy Metabolism in Healthy and Diseased Myocardium) Mice with constitutive deletion (in all tissues) of the gene encoding PPARα (PPARα null mice) exhibit diminished rates of cardiac fatty acid oxidation (FAO) and increased reliance on glucose utilization pathways [7–9]. This shift is mediated, at least in part, by diminished expression of several genes involved in FAO [10] and a concomitant increase in the expression of genes encoding proteins involved in glucose uptake and utilization [7]. At the other end of the metabolic spectrum, we have characterized transgenic mice overexpressing PPARα in a cardiac-restricted manner (MHC-PPARα mice) [8, 11–16]. The expression of many genes involved in fatty acid uptake and utilization is upregulated in MHC-PPARα mice, while the expression of glucose transporter and glycolytic enzymes is strikingly suppressed [11]. Consistent with this pattern of metabolic gene expression, MHC-PPARα mice rely almost exclusively on FAO and use very little glucose [8, 9, 11]. HF 时心肌能量代谢的底物发生改变，由优先利用FA 变为优先利用葡萄糖作为能量代谢的底物。尽管葡萄糖代替FA 氧化，比较消耗每个氧原子产生的ATP 量，有轻微的节约效应，但综上所述，FA 氧化减少并不能完全被葡萄糖氧化增强所代偿，衰竭心肌ATP 再生率全面减少，心肌ATP含量减少，线粒体功能障碍。心肌存在着进行性能量衰竭，最终导致心脏功能的降低。 * Schematic representation of the mechanisms involved in the metabolic dysregulation of AC16 cells treated with tumour necrosis factor-α. Activation of both nuclear factor-κB and p38 mitogen-activated protein kinase pathways by tumour necrosis factor-α mediates, besides a pro-inflammatory profile, the reduction of PGC-1α and PDK4 expression and subsequent increase in glucose oxidation rate. PGC-1α and PDK4 expression is downregulated by tumour necrosis factor