Succinate accumulation impairs cardiac pyruvate dehydrogenase activity through GRP91-dependent and independent signaling pathways: Therapeutic effects of ginsenoside Rb1

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1863

Article

Li, Jia¹  Yang, Yi-Lin¹  Li, Lan-Zhu¹  Zhang, Lei¹  Liu, Qun¹  Liu, Kang²  Li, Ping¹  Liu, Baolin²  Qi, Lian-Wen¹ 

[1] China Pharmaceut Univ, State Key Lab Nat Med, Nanjing, Jiangsu, Peoples R China

[2] China Pharmaceut Univ, Dept Pharmacol Chinese Mat Med, Jiangsu Key Lab TCM Evaluat & Translat Res, Nanjing, Jiangsu, Peoples R China

关键词: Cardiomyocytes;    Ginsenoside Rb1;    GPR91;    Pyruvate dehydrogenase;    Succinate;   

DOI  :  10.1016/j.bbadis.2017.07.017

来源: Elsevier

【 摘 要 】

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.

【 授权许可】

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