Abraham Nader G, Kushida Taketoshi, McClung Jack, Weiss Melvin, Quan Shuo, Lafaro Rocky, Darzynkiewicz Zbigniew, Wolin Michael
Department of Pharmacology, New York Medical College, Valhalla, NY 10595, USA.
Circ Res. 2003 Sep 19;93(6):507-14. doi: 10.1161/01.RES.0000091828.36599.34. Epub 2003 Aug 21.
Heme oxygenase-1 (HO-1) is a stress protein that has been suggested to participate in defense mechanisms against agents that may induce oxidative injury, such as heme and inflammatory molecules. Incubation of endothelial cells in a high-glucose (33 mmol/L) medium for 7 days resulted in a decrease of HO activity by 34% and a decrease in HO-1 and HO-2 proteins compared with cells exposed to low glucose (5 mmol/L) (P<0.05) or cells exposed to mannitol (33 mmol/L). Overexpression of HO-1 was coupled with an increase in HO activity and carbon monoxide synthesis, decreased cellular heme, and acceleration in all phases of the cell cycle (P<0.001). The rate of cell cycle or cell birth rate was increased by 29% (P<0.05) in cells overexpressing HO-1 but decreased by 23% (P<0.05) in cells underexpressing HO-1 compared with control cells. Exposure to high glucose significantly decreased cell-cycle progression in control cells and in cells underexpressing HO-1 but did not decrease cell-cycle progression in cells overexpressing HO-1. High glucose induced p21 and p27 in control cells but not in cells overexpressing HO-1. The addition of tin-mesoporphyrin (SnMP), an inhibitor of HO activity, reversed the HO-1-mediated decrease of p21 and p27 in cells overexpressing HO-1. These findings identify a novel effect of HO-1 on endothelial cell growth and indicate that heme metabolism and HO-1 expression regulate signaling systems in cells exposed to high glucose, which controls cell-cycle progression.
血红素加氧酶-1（HO-1）是一种应激蛋白，有人认为它参与了针对可能诱导氧化损伤的物质（如血红素和炎症分子）的防御机制。与暴露于低葡萄糖（5 mmol/L）的细胞或暴露于甘露醇（33 mmol/L）的细胞相比，内皮细胞在高葡萄糖（33 mmol/L）培养基中孵育7天导致HO活性降低34%，HO-1和HO-2蛋白减少（P<0.05）。HO-1的过表达与HO活性和一氧化碳合成的增加、细胞血红素的减少以及细胞周期各阶段的加速相关（P<0.001）。与对照细胞相比，过表达HO-1的细胞中细胞周期速率或细胞出生率增加了29%（P<0.05），而过低表达HO-1的细胞中则降低了23%（P<0.05）。暴露于高葡萄糖显著降低了对照细胞和过低表达HO-1的细胞中的细胞周期进程，但并未降低过表达HO-1的细胞中的细胞周期进程。高葡萄糖在对照细胞中诱导p21和p27，但在过表达HO-1的细胞中则不然。添加HO活性抑制剂锡-中卟啉（SnMP）可逆转HO-1介导的过表达HO-1的细胞中p21和p27的减少。这些发现确定了HO-！对内皮细胞生长的新作用，并表明血红素代谢和HO-1表达调节暴露于高葡萄糖的细胞中的信号系统，从而控制细胞周期进程。
