Celastrol Prevents Atherosclerosis via Inhibiting LOX-1 and Oxidative Stress

Abstract

Celastrol is a triterpenoid compound extracted from the Chinese herb Tripterygium wilfordii Hook F. Previous research has revealed its anti-oxidant, anti-inflammatory, anti-cancer and immunosuppressive properties. Here, we investigated whether celastrol inhibits oxidized low-density lipoprotein (oxLDL) induced oxidative stress in RAW 264.7 cells. In addition, the effect of celastrol on atherosclerosis in vivo was assessed in apolipoprotein E knockout (apoE−/−) mouse fed a high-fat/high-cholesterol diet (HFC). We found that celastrol significantly attenuated oxLDL-induced excessive expression of lectin-like oxidized low density lipoprotein receptor-1(LOX-1) and generation of reactive oxygen species (ROS) in cultured RAW264.7 macrophages. Celastrol also decreased IκB phosphorylation and degradation and reduced production of inducible nitric oxide synthase (iNOS), nitric oxide (NO) and proinflammatory cytokines such as tumor necrosis factor (TNF)-α and IL-6. Celastrol reduced atherosclerotic plaque size in apoE−/− mice. The expression of LOX-1 within the atherosclerotic lesions and generation of superoxide in mouse aorta were also significantly reduced by celastrol while the lipid profile was not improved. In conclusion, our results show that celastrol inhibits atherosclerotic plaque developing in apoE−/− mice via inhibiting LOX-1 and oxidative stress.

Protective role of n6/n3 PUFA supplementation with varying DHA/EPA ratios against atherosclerosis in mice

“…After fixation, the entire A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT 6 aorta was removed, opened longitudinally from the heart to the iliac arteries, pinned on a black wax pan, and stained with Oil red O to analyze the atherosclerotic plaque burden. Images of the aortas were captured using a SONY DXC-970MD color video camera and were analyzed with the Image-Pro plus program [32].…”

Relationship among IL-6, LDL cholesterol and lipid peroxidation

“…Previous studies demonstrated that ox-LDL uptake through this receptor induces endothelial dysfunction, generates superoxide anions, reduces nitric oxide production, and activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) [16,17]. This receptor is expressed in the aorta of hypertensive, diabetic and hyperlipidemic animals [18], and it is up-regulated in early human atherosclerotic lesions [19]. These results suggest that LOX-1 plays an important role in atherogenesis, by internalizing and degrading ox-LDL, and in inflammatory responses in vivo, raising cellular ox-LDL uptake [20].…”

Tripterine Treatment Improves Endothelial Progenitor Cell Function via Integrin-Linked Kinase

“…Tripterine inhibits the synthesis of peroxynitrite precursors, which are produced by endothelial cells in response to pro-inflammatory stimuli, and is thus implicated in the protection against endothelial barrier dysfunction. Tripterine was shown to inhibit atherosclerotic plaque development in a mouse model through the inhibition of the lectinlike ox-LDL receptor LOX-1 and the reduction of oxidative stress [16]. The atheroprotective effects of tripterine were demonstrated in a recent study investigating the inhibition of resistin induced smooth muscle cell (SMC) migration, which is associated with vascular restenosis [17].…”