POSSIBLE MOLECULAR MECHANISMS FOR PORTAL HYPERTENSION AND THE IMPLICATIONS ON ITS TREATMENT

门静脉高压的可能分子机制及其治疗的意义

• 批准号: 14571204
• 负责人: TOMIKAWA Morimasa
• 金额: $ 1.79万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571204/
• 关键词: portal hypertension; hyperdynamic circulation; intrahepatic vascular resistance; endothelial nitric oxide synthase (eNOS); hepatic stellate cell (HSC); nitric oxide (NO); Rho kinase; Akt; シグナルトランスダクション; ROCK; RHOkinase阻害剤; 肝線維化; 肝硬変治療

Portal hypertension is characterized by the hyperdynamic circulation in the splanchnic organs as well as by the increased intrahepatic vascular resistance. Excessive nitric oxide production by endothelial nitric oxide synthase (eNOS) and elevated tumor necrosis factor-α (TNF-α) are implicated in the development of the systemic hyperdynamic circulation and portal hypertensive (PHT) gastropathy. The increased intrahepatic vascular resistance is associated with a contraction of hepatic stellate cells (HSCs) and a reduction of nitric oxide (NO) production in sinusoidal endothelial cells. HSCs also plays a major role in hepatic fibrogenesis, leading to portal hypertension. However, the molecular mechanisms for these phenomena remain to be elucidated. The aims of our studies are to determine the molecular basis for the hyperdynamic circulation of splanchnic organs and the intrahepatic microcirculatory disturbance.Our present study demonstrates for the first time that : (1)eNOS activation in … More PHT gastric mucosa is due to : (a)increased phosphorylation of eNOS at serine 1177 ; (b)activation of the PI 3-kinase/Akt signaling pathway ; (c)enhanced binding of Akt to eNOS ; and, (2)TNF-α neutralizing antibody reduces phosphorylation of eNOS and activation of the PI 3-kinase/Akt signaling pathway in PHT gastric mucosa to the normal levels. In PHT gastric mucosa elevated TNF-α induces phosphorylation of eNOS at serine 1177 (required for its activation) via activation of the PI 3-kinase/Akt signaling pathway.PHT gastric mucosa is highly susceptible to injury caused by alcohol, aspirin and other noxious factors, but the mechanism is not fully understood. Since such mucosal injury is initially mediated by oxygen free radicals, and since MAP kinase (ERK2) protects against cellular stress and induces cell proliferation, we postulated that oxidative stress-induced ERK2 activation is defective in PHT gastric mucosa. Here we demonstrated that in PHT gastric mucosa, ERK2 activation by oxidative stress is impaired. This impairment is mediated by overexpression of MAP kinase phosphatase-1 (MKP-1), which results from an underlying oxidative state, and is ameliorated by inhibiting MKP-1. Supplementing vitamin E, a free radical scavenger, normalizes MKP-1 expression in PHT gastric mucosa and completely reverses the increased susceptibility to alcohol injury. Our findings provide the molecular mechanism for the pathophysiology of PHT gastropathy and should expedite developing effective non-invasive therapy.In the rat model of liver fibrosis induced by dimethlnitrosamine(DMN), fasudil (a novel specific inhibitor of Rho kinase) conceptation orally reduced fibrosis of the liver in 3 weeks. HSCs activation induced by liver injuary, as shown by the decreased the number of activated HSCs (_-SMA positive cells) and the protein expression_-SMA was also reduced in 3weeks. Moreover, oral administration of fasudil significantly reduced portal pressure of DMN rats at both 1 and 3 weeks, compared to DMN alone. This study indicates that oral administration of fasudil reduce extracellular matrix deposition and portal hypertension in vivo. In vitro experiments showed 1_M fasudil induced HSC apoptosis. The reduction of liver fibrosis and portal hypertension is likely to be induced by inhibition of HSC activation and apoptosis. These points will impact on the new therapiutic drug for cirrhotic patients.The present study demonstrates in cirrhotic rats by the bile duct ligation that (1)Rho kinase signaling and its dawnstream _-SMA protein is upregulated; and (2)the long-term inhibition of Rho kinase with fasudil leads to the reduced contraction of HSCs and the upregulation of eNOS phosphorylation and prevents the microcirculatory disturbance, finally improving the portal hypertension in liver cirrhosis. Less

门静脉高压症是以内脏器官高动力循环和肝内血管阻力增加为特征的。内皮型一氧化氮合酶（eNOS）产生的过量一氧化氮和肿瘤坏死因子-α（TNF-α）的升高与系统性高动力循环和门脉高压性胃病（PHT）的发展有关。肝内血管阻力的增加与肝星状细胞（HSC）的收缩和肝窦内皮细胞中一氧化氮（NO）产生的减少有关。HSC还在肝纤维化中起主要作用，导致门静脉高压。然而，这些现象的分子机制仍有待阐明。本研究首次证实：（1）肝内eNOS激活与肝内微循环障碍有关，提示eNOS激活与肝内微循环障碍有关，提示eNOS激活与肝内微循环障碍有关。 ...更多信息 PHT胃粘膜中eNOS在丝氨酸1177处的磷酸化增加;（B）PI 3-激酶/Akt信号通路的激活;（c）Akt与eNOS的结合增强;和（2）TNF-α中和抗体将PHT胃粘膜中eNOS的磷酸化和PI 3-激酶/Akt信号通路的激活降低至正常水平。在PHT胃粘膜中，TNF-α通过激活PI 3-kinase/Akt信号通路，诱导eNOS在丝氨酸1177处磷酸化，从而导致胃粘膜对酒精、阿司匹林等有害因素的损伤高度敏感，但其机制尚不完全清楚。由于这种粘膜损伤最初是由氧自由基介导的，并且由于MAP激酶（ERK 2）保护细胞免受应激并诱导细胞增殖，因此我们推测氧化应激诱导的ERK 2活化在PHT胃粘膜中是有缺陷的。在这里，我们证明，在PHT胃粘膜，ERK 2激活氧化应激受损。这种损害是由MAP激酶磷酸酶-1（MKP-1）的过度表达介导的，这是由潜在的氧化状态引起的，并通过抑制MKP-1得到改善。补充维生素E，自由基清除剂，使PHT胃粘膜中的MKP-1表达正常化，并完全逆转对酒精损伤的易感性增加。在二甲基亚硝胺（DMN）诱导的大鼠肝纤维化模型中，口服法舒地尔（一种新型的Rho激酶特异性抑制剂）3周后可减轻肝纤维化。肝损伤诱导的HSC活化，表现为活化的HSC（-SMA阳性细胞）数量减少，3周后-SMA蛋白表达也减少。此外，口服法舒地尔显着降低门静脉压力的DMN大鼠在1和3周，与DMN单独。这项研究表明，口服法舒地尔减少细胞外基质沉积和门静脉高压症在体内。体外实验显示1_M法舒地尔可诱导HSC凋亡。肝纤维化和门脉高压的减轻可能是通过抑制HSC的活化和凋亡来诱导的。本研究表明：（1）Rho激酶信号通路及其dawnstream _-SMA蛋白表达上调;和（2）法舒地尔对Rho激酶的长期抑制导致HSC收缩减少和eNOS磷酸化上调并防止微循环障碍，最终改善肝硬化门脉高压。少

项目成果

Abnormal PTEN expression in portal hypertensive gastric mucosa: A key to impaired PI 3‐kinase/Akt activation and delayed injury healing?

• DOI: 10.1096/fj.02-1107fje
• 发表时间: 2003-12
• 期刊: The FASEB Journal
• 作者: K. Tsugawa;Michael K. Jones;T. Akahoshi;W. Moon;Yoshihiko Maewhara;M. Hashizume;I. Sarfeh;A. Tarnawski

肝硬変の合併症 病態解明への新しい視点】門脈圧亢進症(病態生理)

肝硬化并发症：阐明病理的新视角】门静脉高压症（病理生理学）

• 发表时间: 2002
• 期刊: 肝臓 43
• 作者: 赤星朋比古;橋爪誠;川中博文
• 通讯作者: 川中博文

von Hippel Lindau tumor suppressor and HIF-1 {alpha} : new targets of NSAIDs inhibition of hypoxia-induced angiogenesis.

von Hippel Lindau 肿瘤抑制因子和 HIF-1 {α}：NSAID 抑制缺氧诱导的血管生成的新靶点。

• 发表时间: 2002
• 期刊: FASEB J 16
• 作者: Jones MK;Szabo IL;Kawanaka H;et al.
• 通讯作者: et al.

Complications of liver cirrhosis: The pathophysiology of portal hypertension.

肝硬化的并发症：门脉高压的病理生理学。

• 发表时间: 2002
• 期刊: Acta Hepatologica Japonica 43
• 作者: Akahishi T;Hashizume M;Kawanaka H.
• 通讯作者: Kawanaka H.