Lee T S, Saltsman K A, Ohashi H, King G L
Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA 02215.
Proc Natl Acad Sci U S A. 1989 Jul;86(13):5141-5. doi: 10.1073/pnas.86.13.5141.
Hyperglycemia is believed to be the major cause of diabetic vascular complications involving both microvessels and arteries as in the retina, renal glomeruli, and aorta. It is unclear by which mechanism hyperglycemia is altering the metabolism and functions of vascular cells, although changes in nonenzymatic protein glycosylation and increases in cellular sorbitol levels have been postulated to be involved. Previously, we have reported that the elevation of extracellular glucose levels with cultured bovine retinal capillary endothelial cells causes an increase in protein kinase C (PKC) activity of the membranous pool with a parallel decrease in the cytosol without alteration of its total activity. Now we demonstrate that the mechanism for the activation of PKC is due to an enhanced de novo synthesis of diacylglycerol as indicated by a 2-fold increase of [14C]diacylglycerol labeling from [14C]glucose. The elevated diacylglycerol de novo synthesis is secondarily due to increased formation of precursors derived from glucose metabolism; this formation is enhanced by hyperglycemia as substantiated by elevated [3H]glucose conversion into water. This effect of hyperglycemia on PKC is also observed in cultured aortic smooth muscle and endothelial cells and the retina and kidney of diabetic rats, but not in the brain. Since PKC in vascular cells has been shown to modulate hormone receptor turnover, neovascularization in vitro, and cell growth, we propose that this mechanism of enhancing the membranous PKC activities by hyperglycemia plays an important role in the development of diabetic vascular complications.
高血糖被认为是糖尿病血管并发症的主要原因，这些并发症涉及微血管和动脉，如视网膜、肾小球和主动脉。目前尚不清楚高血糖通过何种机制改变血管细胞的代谢和功能，尽管非酶蛋白糖基化的变化和细胞山梨醇水平的升高被认为与之有关。此前，我们报道过，培养的牛视网膜毛细血管内皮细胞外葡萄糖水平升高会导致膜池蛋白激酶C（PKC）活性增加，同时胞质溶胶中的PKC活性平行下降，而其总活性不变。现在我们证明，PKC激活的机制是由于二酰基甘油从头合成增强，这表现为[14C]二酰基甘油标记从[14C]葡萄糖增加了2倍。二酰基甘油从头合成增加继发于葡萄糖代谢衍生的前体形成增加；高血糖会增强这种形成，[3H]葡萄糖转化为水的增加证实了这一点。在培养的主动脉平滑肌和内皮细胞以及糖尿病大鼠的视网膜和肾脏中也观察到了高血糖对PKC的这种作用，但在大脑中未观察到。由于血管细胞中的PKC已被证明可调节激素受体更新、体外新生血管形成和细胞生长，我们认为高血糖增强膜PKC活性的这一机制在糖尿病血管并发症的发展中起重要作用。
