心血管疾患におけるMIFの発現とその役割

MIF的表达及其在心血管疾病中的作用

• 批准号: 14570687
• 负责人: TAKAHASHI Masafumi
• 金额: $ 2.24万
• 依托单位: Shinshu University Graduate School of Medicine (2003)Jichi Medical University (2002)
• 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-14570687/
• 关键词: Cytokine; Atherosclerosis; Ischemic heart disease; Oxidative stress; Inflammation; Cardiomyocyte

Increasing evidence indicates that inflammatory responses play an important role in the pathphysiology of atherosclerosis and ischemic heart diseases. In the present study, we explored the expression and role of macrophage migration inhibitory factor (MIF) that is regulator for inflammatory responses in cardiovascular diseases such as atherosclerosis and ischemic heart diseases.1.Expression of MIF in cardiovascular cellsIn vitro study using cultured rat neonatal cardiomyocytes demonstrated that significant amounts of MIF were produced in response to oxidative stress. This MIF production was mediated through calcium-insensitive and phorbol ester-insensitive protein kinase C (PKC) pathway, suggesting that oxidative stress induced MIF production is mediated by an atypical PKC isoform. The experiments using dominant negative-PKC isoform further suggest that PKC zeta is involved in this pathway.2.Expression of MIF in animal models of cardiac diseasesWe examined neointima formation and perivascular inflammatory cell infiltration induced by a cuff replacement model in MIF-transgenic and MIF knockout mice. Unfortunately, we observed no significant differences of atherosclerosis formation among control B6 mice, MIF-transgenic mice, and MIF-knockout mice.3.Role of MIF in patients with acute myocardial infarctionIn patients with acute myocardial infarction (AMI), plasma MIF levels were markedly elevated during acute stages of AMI, whereas MIF levels in peripheral blood mononuclear cells increased during subacute stages, suggesting that the MIF production in AMI differ between the acute and subacute stages of AMI by the myocardium and inflammatory blood cells, respectively.

越来越多的证据表明，炎症反应在动脉粥样硬化和缺血性心脏病的病理生理过程中起着重要作用。在本研究中，我们探讨了巨噬细胞移动抑制因子(MIF)在动脉粥样硬化和缺血性心脏病等心血管疾病中的表达和作用。1.MIF在心血管细胞中的表达体外培养的大鼠心肌细胞研究表明，氧化应激可产生大量的MIF。这种MIF的产生是通过钙不敏感和佛波酯不敏感的蛋白激酶C(PKC)途径介导的，这表明氧化应激诱导的MIF产生是由非典型的PKC亚型介导的。使用显性负PKC亚型的实验进一步表明PKC Zeta参与了这一途径。2.MIF在心脏疾病动物模型中的表达我们观察了MIF转基因和MIF基因敲除小鼠的袖带置换模型诱导的新生内膜形成和血管周围炎细胞浸润。在急性心肌梗死患者中，急性心肌梗死患者血浆MIF水平在急性心肌梗死急性期显著升高，而外周血单个核细胞MIF水平在亚急性期显著升高，提示急性心肌梗死急性期和亚急性期心肌细胞和炎性血细胞产生的MIF不同。

项目成果

M.Takahashi, E.Kobayashi, U.Ikeda, K.Shimada.et al.: "Elevation of plasma level of macrophage migration inhibitory factor in patients with acute myocardial infarction."Am J Cardiol. 89. 248-249 (2002)

M.Takahashi、E.Kobayashi、U.Ikeda、K.Shimada.et al.：“急性心肌梗死患者巨噬细胞迁移抑制因子血浆水平升高。”Am J Cardiol。

M.Takahashi, E.Kobayashi, U.Ikeda, K.Shimada et al.: "beta-very low density lipoprotein enhances inducible nitric oxide synthase expression in cytokine-stimulated vascular smooth muscle cell"Atherosclerosis. 162. 307-313 (2002)

M.Takahashi、E.Kobayashi、U.Ikeda、K.Shimada 等人：“β-极低密度脂蛋白增强细胞因子刺激的血管平滑肌细胞中诱导型一氧化氮合酶的表达”动脉粥样硬化。

H.Shimizu, M.Takahashi, E.Kobayashi et al.: "Mycophenolate mofetil prevents transplant arteriosclerosis in a rat aortic allograft model."Transplantation. (in press).

H.Shimizu、M.Takahashi、E.Kobayashi 等人：“吗替麦考酚酯在大鼠同种异体移植模型中预防移植动脉硬化。”移植。

Y.Ogata, M.Takahashi, K.Takeuchi, U.Ikeda, K.Shimada, E.Kobayashi et al.: "Anti-apoptotic effect of endothelin-1 in rat cardiomyocytes in vitro."Hypertension. 41. 1156-1163 (2003)

Y.Ogata、M.Takahashi、K.Takeuchi、U.Ikeda、K.Shimada、E.Kobayashi 等：“内皮素 1 对大鼠心肌细胞的体外抗凋亡作用”。高血压。

H.Shimizu, M.Takahashi, E.Kobayashi.et al.: "Mycophenolate mofetil prevents transplant arteriosclerosis in a rat aortic allograft model."Transplantation. (in press).

H.Shimizu、M.Takahashi、E.Kobayashi.et al.：“吗替麦考酚酯在大鼠同种异体移植模型中预防移植动脉硬化。”移植。