Reversal of right ventricular remodeling by dichloroacetate is related to inhibition of mitochondria-dependent apoptosis
Reversal of right ventricular remodeling by dichloroacetate is related to inhibition of mitochondria-dependent apoptosis
复制标题
二氯乙酸逆转右心室重构与抑制线粒体依赖性细胞凋亡有关
DOI：
10.1038/hr.2015.153
复制
发表时间：
2016-05-01
影响因子：
5.4
通讯作者：
Jing, Zhi-Cheng
中科院分区：
文献类型：
--
作者：
Sun, Xiao-Qing;Zhang, Rui;Jing, Zhi-Cheng
大多数肺动脉高压患者死于右心室衰竭（RVF）。右心室（RV）心肌细胞凋亡在RVF中起重要作用，并受线粒体调节。二氯乙酸（DCA）可改善RVF的心功能，但其是否能通过线粒体调节心肌细胞凋亡尚不清楚。在这项研究中，我们研究了DCA对心肌线粒体的影响，线粒体凋亡和RV重塑的其他方面，包括纤维化和毛细血管稀疏。在大鼠中通过单次s.c.注射野百合碱。4周后，开始DCA治疗，每天腹腔注射50、150或2007 mg kg（-1），持续14天。与盐水处理的裂谷热动物相比，DCA处理导致平均肺动脉压和总肺阻力（TPR）降低，心输出量增加。丙酮酸脱氢酶激酶的表达被抑制，而丙酮酸脱氢酶的表达上调与DCA的应用。DCA治疗还与RV线粒体功能恢复以及RV肥大、纤维化、毛细血管稀疏和细胞凋亡减少相关。线粒体依赖的细胞凋亡参与DCA对RV的调控。TPR与RV的主要参数之间缺乏相关性，表明DCA在两个器官系统中的作用是独立的。结论：DCA改善实验性RVF的心功能，部分是通过逆转RV重塑，恢复线粒体功能和调节细胞凋亡。该研究表明，担心DCA治疗会增加RV凋亡是不必要的，并表明DCA在治疗RVF中的潜在作用。
Most patients with pulmonary arterial hypertension die from right ventricular failure (RVF). Right ventricular (RV) myocardial apoptosis has an important role in RVF and is regulated by the mitochondria. Dichloroacetate (DCA) can improve cardiac function in RVF, but whether it can regulate myocardial apoptosis via mitochondria is still unknown. In this study, we investigated the effects of DCA on myocardial mitochondria, the mitochondrial apoptosis and other aspects of RV remodeling, including fibrosis and capillary rarefaction. RVF was induced in rats by a single s.c. injection of monocrotaline. After 4 weeks, DCA treatment was started with i.p. injection of 50, 150 or 2007 mg kg(-1) per day during 14 days. Compared with saline-treated RVF animals, treatment with DCA resulted in decreased mean pulmonary arterial pressure and total pulmonary resistance (TPR), and increased cardiac output. The expression of pyruvate dehydrogenase kinase was suppressed, while pyruvate dehydrogenase expression was upregulated with DCA application. DCA treatment was also associated with restored RV mitochondrial function and a reduction in RV hypertrophy, fibrosis, capillary rarefaction and apoptosis. Mitochondria-dependent apoptosis was involved in DCA regulation of RV. The absent correlation between TPR and main parameters in RV suggests that the effects of DCA in the two organ systems are independent. We conclude that DCA improves cardiac function in experimental RVF partly by reversing RV remodeling, restoring mitochondrial function and regulating mitochondria-dependent apoptosis. The study shows that a fear for increased RV apoptosis with DCA treatment is unnecessary and suggests a potential role of DCA in the treatment of RVF.