Zhang Rui, Jing Zhi-Cheng
State Key Laboratory of Cardiovascular Disease, FuWai Hospital, Peking Union Medical College and Chinese Academy Medical Science, No. 167 Beilishi Road, Beijing 100037, China.
Curr Pharm Des. 2016;22(31):4780-4795. doi: 10.2174/1381612822666160614082712.
The survival of patients with pulmonary arterial hypertension is closely related with right ventricular function. During the progression of right ventricular remodeling, energetic metabolism shifts from oxidative mitochondrial metabolism to glycolysis. In normal physiological conditions, cardiomyocytes use major sources of glucose and fatty acids to sustain a continuous systolic workload and energy supply. This allows the heart to choose the most efficient substrate to response to environmental stimuli. Therefore, ATP production of glucose is the preferred energy source than fatty acids in right ventricular remodeling. However, the metabolic fate of glucose altered because mitochondrial metabolism is actively suppressed. Metabolic shift towards aerobic glycolysis and down-regulation of mitochondrial oxidation, is called the Warburg effect. Studies on animal models and human RVF suggest that there is reduced glucose oxidation and increased glycolysis in both adaptive and maladaptive right ventricular failure. Accordingly, a gate-keeping enzyme, pyruvate dehydrogenase kinase (PDK) is activated and inhibited pyruvate into the mitochondria with increased lactate dehydrogenase. Therefore, augmentation of glucose oxidation is beneficial in right ventricular remodeling and can be achieved by inhibition of PDK and fatty acid oxidation. As a PDK inhibitor, Dicholoracetate (DCA) can reduce pyruvate dehydrogenase phosphorylation and partially restore RV structure and function by promoting glucose and mitochondrial oxidation. Moreover, the partial inhibitors of fatty acid oxidation would be offered the utilization to improve right ventricular function. Although metabolic targeting drugs can be beneficial to right ventricular remodeling, the advantage of modulating metabolic shift into an enhanced clinical performance still remains to be determined.
肺动脉高压患者的生存与右心室功能密切相关。在右心室重塑过程中，能量代谢从氧化线粒体代谢转变为糖酵解。在正常生理条件下，心肌细胞利用葡萄糖和脂肪酸作为主要能量来源来维持持续的收缩工作负荷和能量供应。这使心脏能够选择最有效的底物来应对环境刺激。因此，在右心室重塑中，葡萄糖产生的ATP是比脂肪酸更优先的能量来源。然而，由于线粒体代谢受到主动抑制，葡萄糖的代谢命运发生了改变。向有氧糖酵解的代谢转变以及线粒体氧化的下调，被称为瓦伯格效应。对动物模型和人类右心室功能衰竭的研究表明，在适应性和适应性不良的右心室衰竭中，葡萄糖氧化减少而糖酵解增加。相应地，一种关键酶，丙酮酸脱氢酶激酶（PDK）被激活，并通过增加乳酸脱氢酶抑制丙酮酸进入线粒体。因此，增强葡萄糖氧化对右心室重塑有益，可通过抑制PDK和脂肪酸氧化来实现。作为一种PDK抑制剂，二氯乙酸（DCA）可以减少丙酮酸脱氢酶磷酸化，并通过促进葡萄糖和线粒体氧化部分恢复右心室结构和功能。此外，脂肪酸氧化的部分抑制剂可用于改善右心室功能。尽管代谢靶向药物可能对右心室重塑有益，但将代谢转变调节为增强临床性能的优势仍有待确定。
