SIRT1/Atg5/autophagy are involved in the antiatherosclerosis effects of ursolic acid

Abstract

The purpose of this study was to investigate the antiatherosclerosis effects of ursolic acid (UA) in high-fat diet-fed quails (Coturnix coturnix) and potential mechanism. Quails were treated with high-fat diet (14 % pork oil, 1 % cholesterol w/w) with or without UA (50, 150, or 300 mg/kg/day) for 10 weeks. Serum lipid profile was assessed at 0, 4.5, and 10 weeks. After 10 weeks, serum antioxidant status and morphology of aorta were assessed. Additionally, human umbilical vein endothelial cells (HUVECs) were exposed to 100 μg/ml oxidized low-density lipoprotein (ox-LDL) for 24 h, with or without pretreatment with UA (5, 10 or 20 μM) for 16 h, autophagy inhibitor 3-MA 5 mM for 2 h, or SIRT1 inhibitor EX-527 10 μM for 2 h. Cell viability and oxidative stress status were assessed and autophagy status was determined. Acetylation of lysine residue on Atg5 was assessed with immunoprecipitation. In results, high-fat diet negatively affected serum lipid profile and antioxidant status in quails and induced significant histological changes. Cotreatment with UA remarkably alleviated such changes. In HUVECs, ox-LDL treatment induced significant cytotoxicity along with oxidative stress, while UA cotreatment alleviated such changes significantly. UA treatment induced autophagy, enhanced SIRT1 expression, and decreased acetylation of lysine residue on Atg5. Cotreatment with 3-MA or EX-527 effectively abolished UA's protective effects. In summary, UA exerted antiatherosclerosis effects in quails and protected HUVECs from ox-LDL induced cytotoxicity, and the mechanism is associated with increased SIRT1 expression, decreased Atg5 acetylation on lysine residue, and increased autophagy.

Dietary ursolic acid improves health span and life span in male Drosophila melanogaster

“…There is evidence that srl-overexpressing flies show higher survival rates than wild-type flies following oxidative stress exposure [20]. UA exerts anti-oxidant effects in some species in vivo [44,82], and UA ingestion significantly increased srl expression in male flies as described above. We therefore used a hydrogen-peroxide-based stress assay and measurements of GstS1 enzyme expression to test, whether the UA-mediated increase in life span was mediated partly by an upregulation of antioxidative capacity in male fruit flies.…”

“…Moreover, UA induces endogenous stress-response and alleviates high-fat diet-induced atherogenesis in vitro and in vivo [44]. Additionally, UA induces autophagy in multiple cell culture models [44,45] and in vivo [46]. Both in vitro studies and rodent in vivo studies indicate the anticatabolic activity of UA which counteracts age-related deficits in skeletal muscle strength, quality, and mass and promotes an increase in muscle fiber rejuvenation [47][48][49][50].…”

“…UA may possess anti‐microbial, anti‐inflammatory, redox‐regulating, and antimutagenic properties among others as suggested in various in vitro and in vivo studies (reviewed in ). Moreover, UA induces endogenous stress‐response and alleviates high‐fat diet‐induced atherogenesis in vitro and in vivo . Additionally, UA induces autophagy in multiple cell culture models and in vivo .…”

Matrine attenuates high‐fat diet‐induced in vivo and ox‐LDL‐induced in vitro vascular injury by regulating the PKCα/eNOS and PI3K/Akt/eNOS pathways

“…HUVECs were cultured in DMEM/high glucose medium containing 10% foetal bovine serum, 100 U/mL penicillin and 100 U/mL streptomycin and were incubated at 37°C in 5% CO 2. When the cells had grown to about 80% confluency, the concentration of ox‐LDL (100 μg/mL) was added to the medium and the cells were then cultured for another 24 hours …”

The inhibitor of autophagy SBI‑0206965 aggravates atherosclerosis through decreasing myeloid‑derived suppressor cells

“…Macroautophagy (hereafter referred to as autophagy) is an evolutionarily conserved mechanism which eliminates various intracellular components such as damaged proteins, lipid droplets and organelles. Accumulating evidence suggests autophagy has an important role in the pathogenesis of AS and related disorders (3)(4)(5). Basal autophagy maintains cellular lipid homeostasis (6)(7)(8)(9) and the induction of autophagy has been observed to prevent AS (10)(11)(12)(13).…”