Institute of Clinical Pharmacology and Visceral Research, University of Bern, Bern, Switzerland.
Hepatology. 2011 Jan;53(1):243-52. doi: 10.1002/hep.23978. Epub 2010 Dec 7.
The identification of cellular pathways capable of limiting ischemia/reperfusion (I/R) injury remains a frontier in medicine, and its clinical relevance is urgent. Histidine triad nucleotide binding protein 1 (HINT1) is a tumor suppressor that influences apoptosis. Because apoptotic pathways are a feature of I/R injury, we asked whether Hint1 influences hepatic I/R injury. Hint1(-/-) and C57BL/6 mice were subjected to 70% liver ischemia followed by reperfusion for 3 or 24 hours or to a sham operation. The serum aminotransferase levels, histological lesions, apoptosis, reactive oxygen species, and expression of B cell lymphoma 2-associated X protein (Bax), heme oxygenase 1 (HO-1), interleukin-6 (IL-6), IL-10, tumor necrosis factor-a, Src, nuclear factor kappa B (p65/RelA), and c-Jun were quantified. The responses to toll-like receptor ligands and nicotinamide adenine dinucleotide phosphate oxidase activity in Kupffer cells were compared in Hint1(-/-) mice and C57BL/6 mice. After I/R, the levels of serum aminotransferases, parenchymal necrosis, and hepatocellular apoptosis were significantly lower in Hint1(-/-) mice versus control mice. Furthermore, Bax expression decreased more than 2-fold in Hint1(-/-) mice, and the increases in reactive oxygen species and HO-1 expression that were evident in wild-type mice after I/R were absent in Hint1(-/-) mice. The phosphorylation of Src and the nuclear translocation of p65 were increased in Hint1(-/-) mice, whereas the nuclear expression of phosphorylated c-Jun was decreased. The levels of the protective cytokines IL-6 and IL-10 were increased in Hint1(-/-) mice. These effects increased survival after I/R in mice lacking Hint1. Hint1(-/-) Kupffer cells were less activated than control cells after stimulation with lipopolysaccharides.
The Hint1 protein influences the course of I/R injury, and its ablation in Kupffer cells may limit the extent of the injury.
确定能够限制缺血/再灌注（I/R）损伤的细胞途径仍然是医学的前沿领域，其临床相关性迫在眉睫。组氨酸三核苷酸结合蛋白 1（HINT1）是一种影响细胞凋亡的肿瘤抑制因子。由于凋亡途径是 I/R 损伤的特征，我们想知道 Hint1 是否影响肝 I/R 损伤。将 Hint1（-/-）和 C57BL/6 小鼠进行 70%肝脏缺血，然后再灌注 3 或 24 小时，或进行假手术。检测血清氨基转移酶水平、组织学损伤、细胞凋亡、活性氧（ROS）以及 B 细胞淋巴瘤 2 相关 X 蛋白（Bax）、血红素加氧酶 1（HO-1）、白细胞介素 6（IL-6）、白细胞介素 10（IL-10）、肿瘤坏死因子-a、Src、核因子 kappa B（p65/RelA）和 c-Jun 的表达。比较 Hint1（-/-）小鼠和 C57BL/6 小鼠中 Toll 样受体配体的反应和烟酰胺腺嘌呤二核苷酸磷酸氧化酶活性。在 I/R 后，与对照小鼠相比，血清氨基转移酶、实质坏死和肝细胞凋亡水平在 Hint1（-/-）小鼠中明显降低。此外，在 Hint1（-/-）小鼠中 Bax 表达降低了 2 倍以上，而在野生型小鼠中 I/R 后明显增加的 ROS 和 HO-1 表达在 Hint1（-/-）小鼠中则不存在。Src 的磷酸化和 p65 的核转位在 Hint1（-/-）小鼠中增加，而磷酸化 c-Jun 的核表达减少。在 Hint1（-/-）小鼠中，保护性细胞因子 IL-6 和 IL-10 的水平增加。这些效应增加了缺乏 Hint1 的小鼠的 I/R 后存活率。与对照细胞相比，经脂多糖刺激后，Hint1（-/-）Kupffer 细胞的激活程度较低。
Hint1 蛋白影响 I/R 损伤的过程，其在 Kupffer 细胞中的缺失可能限制损伤的程度。
