Moheimani Fatemeh, Morgan Philip E, van Reyk David M, Davies Michael J
Free Radical Group, The Heart Research Institute, 7 Eliza Street, Newtown NSW, 2042 Australia.
Biochim Biophys Acta. 2010 Jun;1802(6):561-71. doi: 10.1016/j.bbadis.2010.02.007. Epub 2010 Feb 20.
People with diabetes experience chronic hyperglycemia and are at a high risk of developing atherosclerosis and microvascular disease. Reactions of glucose, or aldehydes derived from glucose (e.g. methylglyoxal, glyoxal, or glycolaldehyde), with proteins result in glycation that ultimately yield advanced glycation end products (AGE). AGE are present at elevated levels in plasma and atherosclerotic lesions from people with diabetes, and previous in vitro studies have postulated that the presence of these materials is deleterious to cell function. This accumulation of AGE and glycated proteins within cells may arise from either increased formation and/or ineffective removal by cellular proteolytic systems, such as the proteasomes, the major multi-enzyme complex that removes proteins within cells. In this study it is shown that whilst high glucose concentrations fail to modify proteasome enzyme activities in J774A.1 macrophage-like cell extracts, reactive aldehydes enhanced proteasomal enzyme activities. In contrast BSA, pre-treated with high glucose for 8 weeks, inhibited both the chymotrypsin-like and caspase-like activities. BSA glycated using methylglyoxal or glycolaldehyde, also inhibited proteasomal activity though to differing extents. This suppression of proteasome activity by glycated proteins may result in further intracellular accumulation of glycated proteins with subsequent deleterious effects on cellular function.
糖尿病患者会经历慢性高血糖，并有患动脉粥样硬化和微血管疾病的高风险。葡萄糖或由葡萄糖衍生的醛（如甲基乙二醛、乙二醛或乙醇醛）与蛋白质发生反应会导致糖基化，最终产生晚期糖基化终产物（AGE）。糖尿病患者血浆和动脉粥样硬化病变中AGE水平升高，先前的体外研究推测这些物质的存在对细胞功能有害。细胞内AGE和糖化蛋白的这种积累可能源于细胞蛋白水解系统（如蛋白酶体，一种在细胞内清除蛋白质的主要多酶复合物）形成增加和/或清除无效。本研究表明，虽然高葡萄糖浓度未能改变J774A.1巨噬细胞样细胞提取物中的蛋白酶体酶活性，但反应性醛增强了蛋白酶体酶活性。相比之下，用高葡萄糖预处理8周的牛血清白蛋白（BSA）抑制了胰凝乳蛋白酶样和半胱天冬酶样活性。用甲基乙二醛或乙醇醛糖化的BSA也抑制蛋白酶体活性，不过程度不同。糖化蛋白对蛋白酶体活性的这种抑制可能导致糖化蛋白在细胞内进一步积累，随后对细胞功能产生有害影响。
