Mechanism of Tetramethylpyrazine Analogue CXC195 Inhibition of Hydrogen Peroxide-Induced Apoptosis in Human Endothelial Cells

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概要

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• A tetramethylpyrazine analogue, CXC195, was synthesized by the Boekelheide reaction, in which the second methyl group of tetramethylpyrazine (TMP) was replaced with (4,4′-fluorine) diphenyl-methyl-1-piperazidine, the active group of flunarizine. We have observed protective effects of CXC195 on vascular endothelial cell survival under oxidative stress in previous study. The aim of the present study was to investigate the effects of CXC195 against apoptosis induced by hydrogen peroxide in human umbilical vein endothelial cells (HUVECs). Accordingly, a biochemical approach to elucidate the apoptotic signal pathways was attempted. HUVECs were exposed to 150 μM H2O2 for 12 h, resulting in an increase of apoptotic cells assessed by the nuclear staining assay and flow cytometry. Mitochondrial membrane potential was detected by retention of rhodamine123. The concentration of free intracellular calcium was determined by fura-2/AM fluorometry. Co-incubation with CXC195 reduced the percentage of apoptotic cells and inhibited the loss of mitochondrial membrane potential and intracellular calcium overload induced by H2O2. Induction of p53, the activation of caspase-3 by H2O2 which accompanying downregulation of bcl-2, was blocked by CXC195. In addition, CXC195 clearly improved phosphorylation levels of the antiapoptotic extracellular signal-regulated kinase-1/2 (ERK1/2) in cells undergoing oxidative damage. Moreover, CXC195 showed stronger effects on inhibition of apoptotic cells and loss of mitochondrial membrane potential and activation of phosphorylated ERK1/2 than TMP. These results suggest that CXC195 prevents reactive oxygen species-induced apoptosis through inhibition of the mitochondria-dependent caspase-3 pathway and ERK pathway to show a better beneficial effect in protecting endothelial cells than TMP.

著者

• Ou Yang

  Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University

• Dong Xue

  Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University

• Liu Xin-Yong

  Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University

• Cheng Xian-Chao

  Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University

• Cheng Yan-Na

  Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University

• Yu Lu-Gang

  The Henry Wellcome Laboratory of Molecular and Cellular Gastroenterology, Liverpool Centre for Glyco

• Guo Xiu-Li

  Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University

• Ou Yang

  Department Of Information Security Pukyong National University

• Yu Lu-Gang

  The Henry Wellcome Laboratory of Molecular and Cellular Gastroenterology, Liverpool Centre for Glycobiology, School of Clinical Sciences, University of Liverpool

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