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首页> 外文期刊>American Journal of Physiology >Ether-linked diglycerides inhibit vascular smooth muscle cell growth via decreased MAPK and PI3K/Akt signaling.
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Ether-linked diglycerides inhibit vascular smooth muscle cell growth via decreased MAPK and PI3K/Akt signaling.

机译：醚连接的甘油二酸酯通过降低MAPK和PI3K / Akt信号传导来抑制血管平滑肌细胞的生长。

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Diglycerides (DGs) are phospholipid-derived second messengers that regulate PKC-dependent signaling pathways. Distinct species of DGs are generated from inflammatory cytokines and growth factors. Growth factors increase diacyl- but not ether-linked DG species, whereas inflammatory cytokines predominately generate alkyl, acyl- and alkenyl, acyl-linked DG species in rat mesenchymal cells. These DG species have been shown to differentially regulate protein kinase C (PKC) isotypes. Ester-linked diacylglycerols activate PKC-epsilon and cellular proliferation in contrast to ether-linked DGs, which lead to growth arrest through the inactivation of PKC-epsilon. It is now hypothesized that ether-linked DGs inhibit mitogenesis through the inactivation of ERK and/or Akt signaling cascades. We demonstrate that cell-permeable ether-linked DGs reduce vascular smooth muscle cell growth by inhibiting platelet-derived growth factor-stimulated ERK in a PKC-epsilon-dependent manner. This inhibition is specific to the ERK pathway, since ether-linked DGs do not affect growth factor-induced activation of other family members of the MAPKs, including p38 MAPK and c-Jun NH(2)-terminal kinases. We also demonstrate that ether-linked DGs reduce prosurvival phosphatidylinositol 3-kinase (PI3K)/Akt signaling, independent of PKC-epsilon, by diminishing an interaction between the subunits of PI3K and not by affecting protein phosphatase 2A or lipid (phosphatase and tensin homologue deleted in chromosome 10) phosphatases. Taken together, our studies identify ether-linked DGs as potential adjuvant therapies to limit vascular smooth muscle migration and mitogenesis in atherosclerotic and restenotic models.
机译：甘油二酸酯（DGs）是磷脂衍生的第二信使，它调节PKC依赖的信号通路。 DG的不同物种是由炎性细胞因子和生长因子产生的。生长因子增加二酰基连接的DG种类，但不增加，而炎性细胞因子主要在大鼠间质细胞中产生烷基，酰基和烯基的酰基连接的DG种类。这些DG种类已显示出差异调节蛋白激酶C（PKC）同种型。与醚连接的DG相反，酯连接的二酰基甘油激活PKC-ε和细胞增殖，而后者通过使PKC-ε失活而导致生长停滞。现在假设醚连接的DG通过ERK和/或Akt信号传导级联的失活抑制有丝分裂。我们证明细胞渗透性的醚连接的DGs通过抑制血小板衍生的生长因子刺激的ERK以PKC-ε依赖性方式降低血管平滑肌细胞的生长。这种抑制作用是ERK通路特有的，因为醚连接的DG不影响生长因子诱导的MAPK其他家族成员的激活，包括p38 MAPK和c-Jun NH（2）-末端激酶。我们还证明，通过减少PI3K的亚基之间的相互作用，而不是通过不影响蛋白质磷酸酶2A或脂质（磷酸酶和肌腱蛋白同源物），醚连接的DGs可以减少生存的磷脂酰肌醇3-激酶（PI3K）/ Akt信号传导，独立于PKC-ε 10）号磷酸酶中缺失。两者合计，我们的研究确定以醚连接的DGs作为潜在的辅助疗法，以限制动脉粥样硬化和再狭窄模型中的血管平滑肌迁移和有丝分裂。

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