Furukawa Tetsushi, Bai Chang-Xi, Kaihara Asami, Ozaki Eri, Kawano Takashi, Nakaya Yutaka, Awais Muhammad, Sato Moritoshi, Umezawa Yoshio, Kurokawa Junko
Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.
Mol Pharmacol. 2006 Dec;70(6):1916-24. doi: 10.1124/mol.106.028134. Epub 2006 Sep 19.
Ginseng root is one of the most popular herbs throughout the world and is believed to be a panacea and to promote longevity. It has been used as a medicine to protect against cardiac ischemia, a major cause of death in the West. We have previously demonstrated that ginsenoside Re, a main phytosterol of Panax ginseng, inhibits Ca(2+) accumulation in mitochondria during cardiac ischemia/reperfusion, which is attributable to nitric oxide (NO)-induced Ca(2+) channel inhibition and K(+) channel activation in cardiac myocytes. In this study, we provide compelling evidence that ginsenoside Re activates endothelial NO synthase (eNOS) to release NO, resulting in activation of the slowly activating delayed rectifier K(+) current. The eNOS activation occurs via a nongenomic pathway of each of androgen receptor, estrogen receptor-alpha, and progesterone receptor, in which c-Src, phosphoinositide 3-kinase, Akt, and eNOS are sequentially activated. However, ginsenoside Re does not stimulate proliferation of androgen-responsive LNCaP cells and estrogen-responsive MCF-7 cells, implying that ginsenoside Re does not activate a genomic pathway of sex hormone receptors. Fluorescence resonance energy transfer experiments with a probe, SCCoR (single cell coactivator recruitment), indicate that the lack of genomic action is attributable to failure of coactivator recruitment. Thus, ginsenoside Re acts as a specific agonist for the nongenomic pathway of sex steroid receptors, and NO released from activated eNOS underlies cardiac K(+) channel activation and protection against ischemia-reperfusion injury.
人参根是全球最受欢迎的草药之一，被认为是万灵药并能延年益寿。它已被用作预防心脏缺血的药物，心脏缺血是西方主要的死亡原因。我们之前已证明，人参主要植物甾醇人参皂苷Re在心脏缺血/再灌注期间可抑制线粒体中Ca(2+)的积累，这归因于心肌细胞中一氧化氮(NO)诱导的Ca(2+)通道抑制和K(+)通道激活。在本研究中，我们提供了令人信服的证据，表明人参皂苷Re激活内皮型一氧化氮合酶(eNOS)以释放NO，从而导致缓慢激活的延迟整流钾电流激活。eNOS的激活通过雄激素受体、雌激素受体α和孕激素受体各自的非基因组途径发生，其中c-Src、磷酸肌醇3激酶、Akt和eNOS依次被激活。然而，人参皂苷Re不会刺激雄激素反应性LNCaP细胞和雌激素反应性MCF-7细胞的增殖，这意味着人参皂苷Re不会激活性激素受体的基因组途径。使用探针SCCoR（单细胞共激活剂募集）进行的荧光共振能量转移实验表明，缺乏基因组作用归因于共激活剂募集失败。因此，人参皂苷Re作为性类固醇受体非基因组途径的特异性激动剂，激活的eNOS释放的NO是心脏K(+)通道激活和抗缺血再灌注损伤的基础。
