Abstract
BackgroundAtherosclerosis is a chronic vascular disease posing a great threat to public health. We investigated whether rosuvastatin (RVS) enhanced autophagic activities to inhibit lipid accumulation and polarization conversion of macrophages and then attenuate atherosclerotic lesions.MethodsAll male Apolipoprotein E-deficient (ApoE−/−) mice were fed high-fat diet supplemented with RVS (10 mg/kg/day) or the same volume of normal saline gavage for 20 weeks. The burden of plaques in mice were determined by histopathological staining. Biochemical kits were used to examine the levels of lipid profiles and inflammatory cytokines. The potential mechanisms by which RVS mediated atherosclerosis were explored by western blot, real-time PCR assay, and immunofluorescence staining in mice and RAW264.7 macrophages.ResultsOur data showed that RVS treatment reduced plaque areas in the aorta inner surface and the aortic sinus of ApoE−/− mice with high-fat diet. RVS markedly improved lipid profiles and reduced contents of inflammatory cytokines in the circulation. Then, results of Western blot showed that RVS increased the ratio LC3II/I and level of Beclin 1 and decreased the expression of p62 in aortic tissues, which might be attributed to suppression of PI3K/Akt/mTOR pathway, hinting that autophagy cascades were activated by RVS. Moreover, RVS raised the contents of ABCA1, ABCG1, Arg-1, CD206 and reduced iNOS expression of arterial wall, indicating that RVS promoted cholesterol efflux and M2 macrophage polarization. Similarly, we observed that RVS decreased lipids contents and inflammatory factors expressions in RAW264.7 cells stimulated by ox-LDL, accompanied by levels elevation of ABCA1, ABCG1, Arg-1, CD206 and content reduction of iNOS. These anti-atherosclerotic effects of RVS were abolished by 3-methyladenine intervention. Moreover, RVS could reverse the impaired autophagy flux in macrophages insulted by chloroquine. We further found that PI3K inhibitor LY294002 enhanced and agonist 740 Y-P weakened the autophagy-promoting roles of RVS, respectively.ConclusionsOur study indicated that RVS exhibits atheroprotective effects involving regulation lipid accumulation and polarization conversion by improving autophagy initiation and development via suppressing PI3K/Akt/mTOR axis and enhancing autophagic flux in macrophages.
Highlights
Atherosclerosis is a chronic vascular disease posing a great threat to public health
We investigated the effects of RVS on atherosclerosis development in vivo and in vitro and discovered that RVS intervention significantly attenuated the atherosclerotic lesions, which was attributed to RVS-induced regulation of macrophages lipid accumulation and polarization conversion by enhancing autophagy via mediating PI3K/Akt/mammalian target of rapamycin (mTOR) pathway and autophagic flux
RVS displayed regulatory effects on plaque burden in ApoE−/− mice At first, we examined the size of plaque area in the whole aorta of the ApoE−/− mice to evaluate the effects of RVS on atherosclerosis development
Summary
Atherosclerosis is a chronic vascular disease posing a great threat to public health. We investigated whether rosuvastatin (RVS) enhanced autophagic activities to inhibit lipid accumulation and polarization conversion of macrophages and attenuate atherosclerotic lesions. The potential mechanisms by which RVS mediated atherosclerosis were explored by western blot, real-time PCR assay, and immunofluorescence staining in mice and RAW264.7 macrophages. Atherosclerosis is characterized by ascensive buildup of plaque in the arterial wall with perturbation of lipid metabolism and vascular inflammation [1]. Endothelium dysfunction results in subendothelial accumulation of oxidized low-density lipoprotein (ox-LDL), and transmigration of monocytes into arterial wall where they differentiate into macrophages that engulf excessive ox-LDL to generate lipid-laden foam cells, which triggers the initiation and development of atherosclerosis [1,2,3]. Macrophages produce pro-inflammatory mediators under ox-LDL stimulation, which aggravates the atherosclerotic lesions [4, 5]. The alternatively activated M2 macrophages are generated in response to IL-4 or IL-13, which release anti-inflammatory factors such as IL-10, Arginase-1 and possess anti-atherosclerotic ability [13, 14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
