YC-1 [3-(5’-hydroxymethyl-2’-furyl)-1-benzylindazole] 為一種 soluble guanylate cyclase (sGC) 活化劑，其可以刺激細胞內 cGMP 濃度的增加。本論文主要是 探討本論文主要探討由菲律賓樟樹 (Cinnamomum philippines) 中所分離出來 的成分 cinnamophilin 抑制氧化態低密度脂蛋白 (oxidized low density lipopro tein; ox-LDL) 誘導小鼠腦血管內皮細胞 (cerebral endothelial cell; CEC) 死亡 的機制研究。 Cinnamophilin 以濃度相關方式抑制了 ox-LDL 所引發 CEC 的細胞凋亡現象以及 caspase-9 和 caspase-3 的活化。但是 cinnamophilin (10 µM) 並無法抑制 cytochrome c 或 Smac 由粒線體中釋放到細胞質中，更進 一步， cinnamophilin 並不影響 ox-LDL 所引起的粒線體膜電位的減少。此 外， cinnamophilin 能抑制 ox-LDL 造成的活性氧分子 (reactive oxygen spec ies; ROS) 增加。 GRP78 蛋白的表現代表其內質網壓力增加。 Ox-LDL 以時 間相關增加內質網壓力。 Cinnamophilin 以濃度相關方式明顯抑制 ox-LDL 所引發 GRP78 蛋白質表現量增加。綜合以上， cinnamophilin 抑制 ox-LD L 誘導腦血管內皮細胞凋亡的機制可能是經由抑制 ROS 的增加、內質網壓 力、 caspase-9 和 caspase-3 的活化。因此 cinnamophilin 可能具有發展成 為治療腦血管疾病的潛力。
Cinnamophilin 抑制腦血管內 皮細胞凋亡之作用機轉探討
In this study, we attempted to evaluate the inhibitory mechanism of cinnamophilin, isolates from Cinnamomum philippinese, on oxidized low density lipoprotein (ox-L DL)- induced cerebral endothelial cell (CEC) death. Cinnamophilin inhibited the o x-LDL-induced CEC apoptosis and the activation of caspase-9 and caspase-3 in a c oncentration-dependent manner. However, cinnamophilin did not affect the release of cytochrome c and second-mitochondria-derived activator of caspase (Smac) fro m the mitochondria to the cytoplasm. Furthermore, cinnamophilin (10 µM) did not affect the ox-LDL-induced the loss of mitochondrial membrane potential. In additio n, cinnamophilin concentration-dependently inhibited ox-LDL-induced production of reactive oxygen species (ROS). Ox-LDL increased endoplasmic reticulum (ER) stress, reflected by GRP78 expression, in a time-dependent manner. Cinnamophilin markedly inhibited ox-LDL-induced GRP78 expression in a concentration-depende nt manner. Taken together, the inhibitory mechanism of cinnamophilin on ox-LDL- induced CEC apoptosis may be, at least in part, through suppression of ROS format ion, ER stress, caspase-9, and caspase-3 activation. We conclude that cinnamophili n may have therapeutic potential in cerebrovascular diseases.
