Affiliation:
1. Boston Medical Center, EBRC 820, Diabetes & Metabolism Unit, Section of Endocrinology and Departments of Medicine and Physiology, Boston University School of Medicine, Boston, Massachusetts
2. Cellular Stress Group, MRC Clinical Sciences Center, Imperial College School of Medicine, London, U.K.
Abstract
Apoptosis has been observed in vascular cells, nerve, and myocardium of diabetic humans and experimental animals, although whether it contributes to or is a marker of complications in these tissues is unclear. Previous studies have shown that incubation of human umbilical vein endothelial cells (HUVECs) with 30 vs. 5 mmol/l glucose for 72 h causes a significant increase in apoptosis, possibly related to an increase in oxidative stress. We report here that this increase in apoptosis (assessed morphologically by TdT-mediated dUTP nick- end labeling staining) is preceded (24 h of incubation) by inhibition of fatty acid oxidation, by increases in diacylglycerol synthesis, the concentration of malonyl CoA, and caspase-3 activity, and by decreases in mitochondrial membrane potential and cellular ATP content. In addition, the phosphorylation of Akt in the presence of 150 μU/ml insulin was impaired. No increases in ceramide content or its de novo synthesis were observed. AMP-activated protein kinase (AMPK) activity was not diminished; however, incubation with the AMPK activator 5-aminoimidazole-4-carboxamide-riboside increased AMPK activity twofold and completely prevented all of these changes. Likewise, expression of a constitutively active AMPK in HUVEC prevented the increase in caspase-3 activity. The results indicate that alterations in fatty-acid metabolism, impaired Akt activation by insulin, and increased caspase-3 activity precede visible evidence of apoptosis in HUVEC incubated in a hyperglycemic medium. They also suggest that AMPK could play an important role in protecting the endothelial cell against the adverse effects of sustained hyperglycemia.
Publisher
American Diabetes Association
Subject
Endocrinology, Diabetes and Metabolism,Internal Medicine
Reference54 articles.
1. Ruderman NB, Williamson JR, Brownlee M: Glucose and diabetic vascular disease. FASEB J 6: 2905–2914, 1992
2. Li W, Yanoff M, Liu X, Ye X: Retinal capillary pericyte apoptosis in early human diabetic retinopathy. Chin Med J (Engl) 110:659–663, 1997
3. Kern TS, Tang J, Mizutani M, Kowluru RA, Nagaraj RH, Romeo G, Podesta F, Lorenzi M: Response of capillary cell death to aminoguanidine predicts the development of retinopathy: comparison of diabetes and galactosemia. Invest Ophthalmol Vis Sci 41:3972–3978, 2000
4. Fiordaliso F, Li B, Latini R, Sonnenblick EH, Anversa P, Leri A, Kajstura J: Myocyte death in streptozotocin-induced diabetes in rats is angiotensin II- dependent. Lab Invest 80:513–527, 2000
5. Frustaci A, Kajstura J, Chimenti C, Jakoniuk I, Leri A, Maseri A, Nadal-Ginard B, Anversa P: Myocardial cell death in human diabetes. Circ Res 87:1123–1132, 2000
Cited by
302 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献