High-glucose treatment regulates biological functions of human umbilical vein endothelial cells via Sirt1/FOXO3 pathway
ANNALS OF TRANSLATIONAL MEDICINE
Authors: Chen, Yihui; Wang, Yan; Jiang, Yaping; Zhang, Xiaoyan; Sheng, Minjie
Background: Hyperglycaemia-induced angiogenesis plays an important role in diabetic retinopathy (DR). This study aimed to investigate the role of sirtuin1 (Sirt1)/forkhead box O3 (FOXO3) pathway in the effects of high-glucose on human umbilical vein endothelial cells (HUVECs). Methods: HUVECs were divided into normal control group (5 mM glucose), high glucose group (30 mM), 30 mM glucose + shsirt1 group, 30 mM glucose + Sirt1 over-expression group (30 mM + Sirt1), 30 mM glucose + Sirt1 agonist SRT group, 30 mM glucose + SRT + FOXO3 silencing group (30 mM + SRT + siFOXO3). Cell proliferation, migration, invasion and apoptosis were determined. Results: High glucose treatment reduced the expression of Sirt1 and FOXO3 in HUVECs. However, Sirt1 over-expression or SRT attenuated the high-glucose-induced inhibition of HUVEC proliferation and migration as well as reduced their apoptosis. In contrast, Sirt1 silencing deteriorated the high-glucose induced inhibition of HUVEC proliferation and migration and further increased HUVEC apoptosis. FOXO3 expression increased with the increase in Sirt1 expression, which was accompanied by enhanced cellular functions. These were abolished after FOXO3 silencing. In addition, Sirt1/FOXO3 regulated I IUVEC activities via peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha). Conclusions: Sirt1/FOXO3 pathway is essential for the survival of endothelial cells under high-glucose and plays an important role in the development of diabetes-induced retinal vascular endothelial injury.
Ketogenic diet induces skeletal muscle atrophy via reducing muscle protein synthesis and possibly activating proteolysis in mice
Authors: Nakao, Reiko; Abe, Tomoki; Yamamoto, Saori; Oishi, Katsutaka
Ketogenic diets (KD) that are very high in fat and low in carbohydrates are thought to simulate the metabolic effects of starvation. We fed mice with a KD for seven days to assess the underlying mechanisms of muscle wasting induced by chronic starvation. This diet decreased the weight of the gastrocnemius (Ga), tibialis anterior (TA) and soleus (Sol) muscles by 23%, 11% and 16%, respectively. The size of Ga, TA, Sol muscle fibers and the grip strength of four limbs also significantly declined by 20%, 28%, 16% and 22%, respectively. The muscle atrophy-related genes Mafbx, Murf1, Foxo3, Lc3b and Klf15 were upregulated in the skeletal muscles of mice fed with the KD. In accordance with the reduced expression of anabolic genes such as Igf1, surface sensing of translation (SUnSET) analyses of fast-twitch Ga, TA and Sol muscles revealed that the KD suppressed muscle protein synthesis. The mRNA expression of oxidative stress-responsive genes such as Sod1 was significantly increased in all muscles examined. In addition to hypercorticosteronemia, hypoinsulinemia and reduced IGF-1, oxidative stress might also be involved in KD-induced muscle atrophy. Feeding mice with a KD is a novel experimental animal model of muscle-wasting induced by chronic starvation.