期刊
ATHEROSCLEROSIS
卷 247, 期 -, 页码 207-217出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.atherosclerosis.2016.01.043
关键词
Autophagy; Endothelial cells; Diabetes mellitus
资金
- National Heart, Lung, and Blood Institute [HL81587, HL11539]
- NIH [T32 HL007224, HL102299, HL109790, HL081587, HL115775]
- Boston University Medical Center Leadership Program in Vascular Medicine [K12 HL083781]
- American Heart Association Postdoctoral Fellowship [12POST11780028]
Background: Endothelial dysfunction contributes to cardiovascular disease in diabetes mellitus. Autophagy is a multistep mechanism for the removal of damaged proteins and organelles from the cell. Under diabetic conditions, inadequate autophagy promotes cellular dysfunction and insulin resistance in non-vascular tissue. We hypothesized that impaired autophagy contributes to endothelial dysfunction in diabetes mellitus. Methods and results: We measured autophagy markers and endothelial nitric oxide synthase (eNOS) activation in freshly isolated endothelial cells fromdiabetic subjects (n = 45) and non-diabetic controls (n = 41). p62 levels were higher in cells from diabetics (34.2 +/- 3.6 vs. 20.0 +/- 1.6, P = 0.001), indicating reduced autophagic flux. Bafilomycin inhibited insulin-induced activation of eNOS (64.7 +/- 22% to -47.8 +/- 8%, P = 0.04) in cells from controls, confirming that intact autophagy is necessary for eNOS signaling. In endothelial cells from diabetics, activation of autophagy with spermidine restored eNOS activation, suggesting that impaired autophagy contributes to endothelial dysfunction (P = 0.01). Indicators of autophagy initiation including the number of LC3-bound puncta and beclin 1 expression were similar in diabetics and controls, whereas an autophagy terminal phase indicator, the lysosomal protein Lamp2a, was higher in diabetics. In endothelial cells under diabetic conditions, the beneficial effect of spermidine on eNOS activation was blocked by autophagy inhibitors bafilomycin or 3-methyladenine. Blocking the terminal stage of autophagy with bafilomycin increased p62 (P = 0.01) in cells from diabetics to a lesser extent than in cells from controls (P = 0.04), suggesting ongoing, but inadequate autophagic clearance. Conclusion: Inadequate autophagy contributes to endothelial dysfunction in patients with diabetes and may be a target for therapy of diabetic vascular disease. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
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