Succinate accumulation impairs cardiac pyruvate dehydrogenase activity through GRP91-dependent and independent signaling pathways: Therapeutic effects of ginsenoside Rb1
Succinate accumulation impairs cardiac pyruvate dehydrogenase activity through GRP91-dependent and independent signaling pathways: Therapeutic effects of ginsenoside Rb1
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琥珀酸积累通过 GRP91 依赖性和独立信号通路损害心脏丙酮酸脱氢酶活性：人参皂苷 Rb1 的治疗作用
DOI：
10.1016/j.bbadis.2017.07.017
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发表时间：
2017-11-01
影响因子：
6.2
通讯作者：
Qi, Lian-Wen
中科院分区：
文献类型：
--
作者：
Li, Jia;Yang, Yi-Lin;Qi, Lian-Wen
改变的线粒体氧化增加了代谢紊乱中心肌缺血/再灌注（I/R）损伤的脆弱性。然而，负责功能障碍的代谢信号仍然部分未知。我们试图测试是否缺氧琥珀酸积累可以抑制丙酮酸脱氢酶（PDH）的活性，随后加重I/R损伤。结果表明，饱和脂肪酸棕榈酸酯刺激增加心肌细胞中的脂肪酸氧化并诱导缺氧，导致琥珀酸积累。胞内琥珀酸通过上调丙酮酸脱氢酶激酶4（PDK 4）表达诱导缺氧诱导因子-la（HIF-1 α）表达并损害PDH活性。荧光素酶报告基因分析表明，琥珀酸通过基因启动子诱导以HIF-1 α依赖的方式增加PDK 4的表达。棕榈酸还诱导琥珀酸释放到细胞外空间。通过激活GRP 91，细胞外琥珀酸诱导PKC δ易位到线粒体，并进一步加剧PDH损伤。这些结果表明，琥珀酸通过GPR 91依赖性和非依赖性途径损害PDH活性。人参皂苷Rb 1（从人参中分离的主要化合物）和曲美他嗪（脂肪酸β-氧化抑制剂）通过阻断琥珀酸酯相关的HIF-1 α激活和GPR 91信号传导来防止心肌细胞中缺氧琥珀酸酯积累并改善PDH活性。Rb 1和曲美他嗪通过提高PDH活性，预防心肌酸化，改善线粒体功能障碍，从而减少缺氧/复氧损伤时的细胞凋亡。在离体工作大鼠心脏灌注棕榈酸和高脂饮食喂养的小鼠，早期干预的Rb 1和曲美他嗪减少琥珀酸的生产和resultively增加心脏缺血/再灌注损伤的阻力。总之，我们的研究结果表明，通过靶向抑制琥珀酸积累诱导的PDH损伤的早期干预是减轻I/R损伤的有效策略。
Altered mitochondrial oxidation increases vulnerability to cardiac ischemia/reperfusion (I/R) injury in metabolic disorders. However, the metabolic signaling responsible for the dysfunction remains partly unknown. We sought to test whether or not hypoxic succinate accumulation could inhibit pyruvate dehydrogenase (PDH) activity and subsequently aggravate I/R injury. Results showed that saturated fatty acid palmitate stimulation increased fatty acid oxidation and induced hypoxia in cardiomyocytes, leading to succinate accumulation. Intracellular succinate induced hypoxia inducible factor-la (HIF-l alpha) expression and impaired PDH activity via upregulation of pyruvate dehydrogenase kinase 4 (PDK4) expression. Luciferase reporter assay showed that succinate increased PDK4 expression through gene promoter induction in a HIF-1 alpha-dependent manner. Palmitate also induced the release of succinate into extracellular space. By activating GRP91, extracellular succinate induced the translocation of PKC delta to mitochondria and further exacerbated PDH impairment. These results demonstrated that succinate impaired PDH activity via GPR91-dependent and independent pathways. Ginsenoside Rb1 (a major compound isolated from ginseng) and trimetazidine (fatty acid beta-oxidation inhibitor) prevented hypoxic succinate accumulation in cardiomyocytes and improved PDH activity by blocking succinate-associated HIF-l alpha activation and GPR91 signaling. Through improving PDH activity, Rb1 and trimetazidine prevented cardiac acidification, ameliorated mitochondrial dysfunction and thereby reduced apoptosis during hypoxia/reoxygenation insult. In isolated working rat hearts perfused with palmitate and in high-fat diet-fed mice, early intervention of Rb1 and trimetazidine reduced succinate production and resultantly increased heart resistance to ischemia/reperfusion injury. Taken together, our findings demonstrated that early intervention by targeting inhibition of succinate accumulation-induced PDH impairment is an effective strategy to alleviate I/R injury.