Liu Qinlong, Rehman Hasibur, Krishnasamy Yasodha, Lemasters John J, Zhong Zhi
Department of Drug Discovery & Biomedical Sciences, Medical University of South CarolinaCharleston 29425, SC, USA.
The Second Affiliated Hospital of Dalian Medical UniversityDalian, Liaoning Province, China.
Int J Physiol Pathophysiol Pharmacol. 2017 Jun 15;9(3):69-83. eCollection 2017.
Permeant cGMP analogs prevent the mitochondria permeability transition (MPT) . In this study, we explored whether 8-pCPT-cGMP prevents the MPT and decreases post-transplant damage to fatty partial liver grafts (FPG) . Rats were fed a control or high-fat, high-fructose diet for 2-week. Lean and fatty liver explants were reduced in size to ~35% and stored in the University of Wisconsin solution with and without 8-pCPT-cGMP (300 µM) for 2 h. After transplantation, alanine aminotransferase release (indicator of hepatocellular injury), hyperbilirubinemia (indicator of poor liver function), and cell death were all higher in FPG than in lean partial grafts (LPG). Liver regeneration increased in LPG but was suppressed in FPG. 8-pCPT-cGMP blunted graft injury, improved liver regeneration and function, and increased survival of FPG. Hepatic mitochondrial depolarization detected by intravital multiphoton microscopy of rhodamine 123 in living rats was ~3.5-fold higher in FPG than in LPG. 8-pCPT-cGMP decreased mitochondrial depolarization in FPG almost to the level of LPG. Activation of mammalian target of rapamycin (mTOR), an energy sensitive kinase that stimulates cell proliferation and growth, and p70S6 kinase, a downstream signaling molecule of mTOR, was increased in LPG but suppressed in FPG. 8-pCPT-cGMP restored the activity of mTOR and p70S6 kinase in FPG. 8-pCPT-cGMP also increased activation of cAMP response element-binding protein (CREB) and expression of cyclins D1 and E in FPG. Non-alcoholic steatosis increases injury and suppresses regeneration after partial liver transplantation, at least in part, due to more severe mitochondrial dysfunction. Protection of mitochondria with a cGMP analog effectively improves outcomes of FPG transplantation.
可渗透的环鸟苷酸（cGMP）类似物可防止线粒体通透性转换（MPT）。在本研究中，我们探讨了8 - 对氯苯硫基 - cGMP是否能防止MPT并减少移植后对脂肪性部分肝移植（FPG）的损伤。大鼠分别给予对照饮食或高脂高果糖饮食2周。将瘦肝和脂肪肝外植体的大小缩减至约35%，并分别置于含有和不含有8 - 对氯苯硫基 - cGMP（300 μM）的威斯康星大学溶液中保存2小时。移植后，FPG中的丙氨酸转氨酶释放（肝细胞损伤指标）、高胆红素血症（肝功能不良指标）和细胞死亡均高于瘦部分肝移植（LPG）。LPG中的肝再生增加，但FPG中的肝再生受到抑制。8 - 对氯苯硫基 - cGMP减轻了移植损伤，改善了肝再生和功能，并提高了FPG的存活率。在活体大鼠中，通过对罗丹明123进行活体多光子显微镜检测发现，FPG中的肝线粒体去极化比LPG高约3.5倍。8 - 对氯苯硫基 - cGMP使FPG中的线粒体去极化几乎降低至LPG的水平。雷帕霉素靶蛋白（mTOR）是一种能量敏感激酶，可刺激细胞增殖和生长，其激活以及mTOR的下游信号分子p70S6激酶在LPG中增加，但在FPG中受到抑制。8 - 对氯苯硫基 - cGMP恢复了FPG中mTOR和p70S6激酶的活性。8 - 对氯苯硫基 - cGMP还增加了FPG中环磷酸腺苷反应元件结合蛋白（CREB）的激活以及细胞周期蛋白D1和E的表达。非酒精性脂肪变性至少部分由于更严重的线粒体功能障碍，增加了部分肝移植后的损伤并抑制了再生。用cGMP类似物保护线粒体可有效改善FPG移植的结果。
