Physiological and pathophysiological roles of the S1P signaling system : an in vivo study

S1P信号系统的生理和病理生理作用：体内研究

• 批准号: 16590221
• 负责人: TAKUWA Noriko
• 金额: $ 2.24万
• 依托单位: Kanazawa University Graduate School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590221/
• 关键词: sphingosine-1-phosphate; sphingosine kinase; cardiac fibrosis; oxidative stress; low molecular weightG proteins; 血小板; モデル動物; 遺伝子改変マウス; 心筋障害; G蛋白共役型受容体; 心筋; 細胞内情報伝達; 浸潤; 細胞運動; 転移

The sphingosine-1-phosphate (S1P) signaling system plays crucial roles in diverse biological phenomena, which include embryonic vascular maturation and lymphocyte trafficking. It is also implicated in development of certain diseases such as cancer. In an attempt to elucidate pathophysiological role, if any, of the S1P signaling system, we have generated transgenic (TG) mice that overexpress SPHK1 in diverse tissues, with up to several ten fold increases in the enzymatic activity. Although TG x TG matings yielded a slightly reduced litter size, the TG mice grew normally without any obvious abnormality. Notably, TG mice with a high but not a low level of SPHK1 expression in the heart showed age-dependent, progressive cardiac fibrosis. Transgenic heart tissues showed embryonic gene upregulation, elevated Rac1 and RhoA activities and increased oxidative stress. Treatment of TG mice with an HMG-CoA reductase inhibitor or an antioxidant N-2-mercaptopropyonylglycine, but not an angiotensin II type 1 receptor blocker, resulted in alleviation of cardiac fibrosis. TG mice also developed modest renal glomerular dysfunction with age. Unexpectedly, the TG mice did not show a propensity for spontaneous malignancy or reduced lifespan as compared to the wild type littermates. These results provide evidence for a pathophysiological role of SPHK1 in cardiac remodeling and glomerular injury.

鞘氨醇-1-磷酸(S1P)信号系统在胚胎血管成熟和淋巴细胞转运等多种生物学现象中发挥着重要作用。它还与某些疾病的发展有关，如癌症。为了阐明S1P信号系统的病理生理作用，我们培育了在不同组织中过表达SPHK1的转基因(TG)小鼠，酶活性增加了数十倍。虽然Tg×Tg配对的小鼠产仔数略有减少，但Tg小鼠生长正常，没有明显的异常。值得注意的是，心脏中SPHK1表达水平高但不低的TG小鼠表现出年龄依赖性的进行性心脏纤维化。转基因心脏组织显示胚胎基因上调，rac1和RhoA活性升高，氧化应激增加。用HMG-CoA还原酶抑制剂或抗氧化剂N-2-巯基丙基甘氨酸治疗TG小鼠，但不用血管紧张素II 1型受体阻滞剂，结果是减轻了心肌纤维化。随着年龄的增长，转基因小鼠也出现了轻度的肾小球功能障碍。出乎意料的是，与野生型小鼠相比，转基因小鼠没有表现出自发恶性的倾向或寿命缩短。这些结果为SPHK1在心脏重构和肾小球损伤中的病理生理作用提供了证据。

项目成果

Class II phosphoinositide 3-kinase alpha-isoform regulates Rho, myosin phosphatase and contraction in vascular smooth muscle.

II 类磷酸肌醇 3-激酶 α-异构体调节 Rho、肌球蛋白磷酸酶和血管平滑肌的收缩。

• 发表时间: 2006
• 期刊: Biochem J. 394(Pt 3)
• 作者: Wang Y;Yoshioka K;Azam MA;Kimura T;Kuwaki T;Takuwa Y.
• 通讯作者: Takuwa Y.

Rho-dependent, Rho kinase-independent inhibitory regulation of Rac and cell migration by LPA1 receptor in Gi-inactivated CHO cells

• DOI: 10.1016/j.yexcr.2006.02.020
• 发表时间: 2006-06-10
• 期刊: EXPERIMENTAL CELL RESEARCH
• 影响因子: 3.7
• 作者: Sugimoto, Naotoshi;Takuwa, Noriko;Takuwa, Yoh
• 通讯作者: Takuwa, Yoh

Blood lipid mediator sphingosine-1-phosphere potently stimulates platelet-derived growth factor-A and -B chein

血脂介质 sphingosine-1-phosphere 有效刺激血小板衍生生长因子-A 和-B chein

• 发表时间: 2004
• 期刊: J.Biol.Chem. 279(13)
• 作者: Usui;S.;et al.
• 通讯作者: et al.

Inhibition of Rac activation as a mechanism for negativeregulation of actin cytoskeletal reorganization and cell motility by cyclic AMP.

抑制 Rac 激活作为环 AMP 负调节肌动蛋白细胞骨架重组和细胞运动的机制。

• 发表时间: 2005
• 期刊: Biochem J 385
• 作者: S. Nagasawa;N. Takuwa;N. Sugimoto;H. Mabuchi;Y. Takuwa
• 通讯作者: Y. Takuwa

Rho-dependent, Rho kinase-independent inhibitory regulation of Rac and cell migration by LPA_1 receptor in G_i-inactivated CHO sells

G_i 失活 CHO 中 LPA_1 受体对 Rac 和细胞迁移的 Rho 依赖性、Rho 激酶非依赖性抑制调节

• 发表时间: 2006
• 期刊: ExP.Cell Res (In Press)
• 作者: R.Zheng;A.Iwase;R.Shen;OB.Goodman Jr;N.Sugimoto;Y.Takuwa;DJ.Lerner;DM.Nanus;Atsuhiro Tanabe;Zheng R;多久和 陽;N.Sugimoto et al.
• 通讯作者: N.Sugimoto et al.