School of Science, Faculty of Science & Engineering, The University of Waikato, Hamilton, New Zealand.
Cell Stress Chaperones. 2018 Jul;23(4):519-525. doi: 10.1007/s12192-017-0858-x. Epub 2017 Nov 13.
A non-resolving inflammation of the endothelium is recognised to be an important process leading to atherosclerosis. In diabetes, this process is thought to account for a significant number of cardiovascular disease-associated death and disability. However, the molecular mechanisms by which diabetes contributes to endothelial inflammation remain to be established. Whilst there is some evidence linking hyperglycaemia-induced reactive oxygen species (ROS) formation by the mitochondrial electron-transport chain to oxidative stress, cellular injury and apoptosis in the endothelium, a clear link to endothelium inflammation has not yet been established. The mitochondrial molecular stress protein Hsp60 is known to be secreted from mammalian cells and is capable of activating pro-inflammatory mediators on target cells expressing Toll-like receptors (TLRs). Hsp60 is also known to be elevated in serum of diabetes patients and has been shown to be upregulated by hyperglycaemic growth conditions in cultured human HeLa cells. This study shows that Hsp60 induced in human acute monocyte leukaemia cell line (THP-1) cells grown under hyperglycaemic conditions (25 mM glucose) was able to be secreted into growth media. Furthermore, the secretion of Hsp60 from THP-1 cells was able to be inhibited by 5,5-(N-N-dimethyl)-amiloride hydrochloride (DMA), an exosomal inhibitor. Interestingly, the conditioned media obtained from THP-1 cells grown in the presence of 25 mM glucose was able to induce the secretion of TNF-α in human vascular endothelium cell line (HUVEC). When conditioned media was immuno-depleted of Hsp60, there was a significant reduction in the release of TNF-α from the HUVEC cells. This suggests that a potential link may exist between hyperglycaemia-induced expression of Hsp60 in monocyte cells and vascular inflammation. Circulating levels of Hsp60 due to mitochondrial stress in diabetes patients could therefore be an important modulator of inflammation in endothelial cells and thus contribute to the increased incidences of atherosclerosis in diabetes mellitus.
内皮细胞的持续炎症被认为是导致动脉粥样硬化的重要过程。在糖尿病中，这一过程被认为是导致大量心血管疾病相关死亡和残疾的原因。然而，糖尿病导致内皮炎症的分子机制仍有待确定。虽然有一些证据表明，线粒体电子传递链引起的高血糖诱导的活性氧（ROS）形成与内皮细胞的氧化应激、细胞损伤和细胞凋亡有关，但尚未明确与内皮炎症的联系。已知哺乳动物细胞分泌线粒体分子应激蛋白 Hsp60，并且能够激活表达 Toll 样受体（TLR）的靶细胞中的促炎介质。Hsp60 的血清水平也已知在糖尿病患者中升高，并已显示在培养的人 HeLa 细胞中由高血糖生长条件上调。本研究表明，在高血糖条件（25mM 葡萄糖）下生长的人急性单核细胞白血病细胞系（THP-1）细胞中诱导的 Hsp60 能够分泌到生长培养基中。此外，THP-1 细胞中 Hsp60 的分泌可以被 5,5-（N-N-二甲基）阿米洛利盐酸盐（DMA）抑制，DMA 是一种外体抑制剂。有趣的是，在存在 25mM 葡萄糖的条件下生长的 THP-1 细胞获得的条件培养基能够诱导人血管内皮细胞系（HUVEC）中 TNF-α的分泌。当条件培养基中免疫耗尽 Hsp60 时，HUVEC 细胞中 TNF-α的释放显著减少。这表明单核细胞中高血糖诱导的 Hsp60 表达与血管炎症之间可能存在潜在联系。因此，糖尿病患者线粒体应激导致的循环 Hsp60 水平可能是内皮细胞炎症的重要调节剂，并导致糖尿病中动脉粥样硬化发生率的增加。
