Restoration of autophagy reduces diabetes-induced endothelial dysfunction

医学 自噬 内皮功能障碍 糖尿病 重症监护医学 内科学 内分泌学 细胞凋亡 生物化学 化学
作者
Maurizio Forte,Sonia Schiavon,Leonardo Schirone,Lia D’Ambrosio,Daniele Vecchio,Giacomo Frati,Sebastiano Sciarretta
出处
期刊:European Heart Journal [Oxford University Press]
卷期号:45 (Supplement_1)
标识
DOI:10.1093/eurheartj/ehae666.3852
摘要

Abstract Introduction Diabetes leads to endothelial dysfunction, a main determinant of several cardiovascular diseases. The molecular mechanisms underlying the effects of hyperglycemia in endothelial cells are not fully characterized. Autophagy, the intracellular process by which the cell digests and recycles senescent or damaged cytoplasmic elements, exerts cardiovascular protective effects, limiting cardiac and vascular injury in the presence of stress. However, it is unclear how hyperglycemia modulates autophagy in endothelial cells. Purpose In this study, we elucidated the role of autophagy in vascular damage induced by diabetes. We also tested whether the restoration autophagy attenuates diabetes-induced endothelial damage. Methods We evaluated the effects of high-glucose (HG, 30 mM for 6 and 24 hours) on markers of endothelial function, autophagy, autophagic flux, and mitophagy in human umbilical endothelial cells (HUVEC) in vitro and in mesenteric arteries from wild-type mice (WT) ex vivo. We tested the effects of autophagy reactivation using the natural polyamine spermidine or ATG7 overexpression (ATG7ov) on apoptosis and angiogenesis in HUVEC treated with HG. Vascular reactivity experiments in the presence of autophagy activation were performed in HG-treated mouse mesenteric arteries and human saphenous veins from patients with peripheral artery disease. Finally, we evaluated the level of autophagy in the mammary arteries of newly discovered diabetic patients undergoing coronary artery bypass graft surgery. Results We found that HG reduces autophagy (0.6 fold p<0.05) and mitophagy (1.5 fold p<0.001) in HUVECs. We also demonstrated that endothelial cells undergoing hyperglycemia fail to activate autophagy under hypoxic conditions (0.6 fold p<0.05). Reactivation of autophagy by ATG7ov rescues apoptosis (0.52 fold p<0.05) and angiogenesis (2.3 fold p<0.05) in HUVEC treated with HG. We further observed that HG exacerbates endothelial dysfunction in a mouse model of genetic inhibition (Beclin 1 +/- mice), compared to WT mice (-19.16 % +-4.97 SEM vs -48.39 % +-2.18 SEM p<0.001). Mechanistically, HG increases cellular acetylation status (0.7 fold p<0.05) and activates p300 (1 fold p<0.05), an autophagy inhibitor. ATG7ov or spermidine, a p300 inhibitor, rescue endothelial-dependent relaxation in mesenteric arteries of WT mice treated with HG (ATG7ov -62.48 % +-5.16 SEM; SP -63.01 +-3.22 SEM; HG -40.67 % +-3.82 p<0.001). Finally, we observed reduced levels of autophagy in mammary arteries from diabetic patients and demonstrated that SP improves vascular function in human saphenous veins (-37.6 % +-12.76 SEM vs -12.52 % +-5.6 SEM p<0.001). Conclusion Our results suggest that the impairment of autophagy is a strong contributor of diabetes induced-endothelial dysfunction. Targeting autophagy may represent a valid therapeutic strategy to counteract the cardiovascular consequences of metabolic stress.

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