心血管疾患におけるMIFの発現とその役割

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学中起着重要作用。在本研究中，我们探讨了巨噬细胞迁移抑制因子（macrophage migration inhibitory factor， MIF）在动脉粥样硬化和缺血性心脏病等心血管疾病中炎症反应的调节因子的表达和作用。MIF在心血管细胞中的表达利用培养的大鼠新生心肌细胞进行的体外研究表明，氧化应激反应产生了大量的MIF。这种MIF的产生是通过钙不敏感和磷酯不敏感蛋白激酶C （PKC）途径介导的，这表明氧化应激诱导的MIF的产生是由一种非典型PKC亚型介导的。利用显性负PKC异构体的实验进一步表明PKC zeta参与了这一途径。MIF在心脏疾病动物模型中的表达我们在MIF转基因小鼠和MIF敲除小鼠中检测了袖带置换模型诱导的新内膜形成和血管周围炎症细胞浸润。不幸的是，我们观察到B6小鼠、mif转基因小鼠和mif敲除小鼠在动脉粥样硬化形成方面没有显著差异。MIF在急性心肌梗死（AMI）患者中的作用急性心肌梗死（AMI）患者血浆MIF水平在急性期显著升高，而外周血单核细胞MIF水平在亚急性期升高，提示AMI急性和亚急性期心肌细胞和炎性血细胞产生的MIF不同。

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.