Enhancement of Autophagy by Simvastatin through Inhibition of Rac1-mTOR Signaling Pathway in Coronary Arterial Myocytes

Yu, Weiwei; Li, Xiang; Xu, Ming; Abais, Justine M.; Chen, Yang; Riebling, Christopher R.; Boini, Krishna M.; Li, Pin Lan; Zhang, Yang

doi:10.1159/000350111

Cited by 119 publications

(115 citation statements)

References 46 publications

Supporting

Mentioning

101

Contrasting

Order By: Relevance

“…It was demonstrated that statins improve bacterial clearance by the host and improve the efficacy of TB drugs by promoting autophagy through inhibition of the HMG-CoA reductase pathway (Parihar et al, 2014). Furthermore, there are some reports claiming that statins also enhance autophagy in an mTOR-dependent way by inhibiting the RAC1-mTOR signaling pathway (Wei et al, 2013). The full mechanisms behind the autophagy-inducing effects of statins are still not fully elucidated; however, the effects observed from statin administration are promising and may provide another possible complement to TB therapy.…”

Section: Arg677trp (C2029t)mentioning

confidence: 99%

Autophagy in the Fight Against Tuberculosis

Bento

Empadinhas

Mendes

2015

DNA and Cell Biology

View full text Add to dashboard Cite

Tuberculosis (TB), a chronic infectious disease mainly caused by the tubercle bacillus Mycobacterium tuberculosis, is one of the world's deadliest diseases that has afflicted humanity since ancient times. Although the number of people falling ill with TB each year is declining, its incidence in many developing countries is still a major cause of concern. Upon invading host cells by phagocytosis, M. tuberculosis can replicate within infected cells by arresting the maturation of the phagosome whose function is to target the pathogen for elimination. Host cells have mechanisms of controlling this evasion by inducing autophagy, an elaborate cellular process that targets bacteria for progressive elimination, decreasing bacterial loads within infected cells. In addition, autophagy activation also aids in the control of inflammation, contributing to a more efficient innate immune response against M. tuberculosis. Several innovative TB therapies have been envisaged based on autophagy manipulation, with some of them revealing high potential for future clinical trials and eventual implementation in healthcare systems. Thus, this review highlights the recent advances on the innate immune response regulation by autophagy upon M. tuberculosis infection and the promising new autophagy-based therapies for TB. Mycobacterium tuberculosis: Biology and Infection

show abstract

Section: Arg677trp (C2029t)mentioning

confidence: 99%

Autophagy in the Fight Against Tuberculosis

Bento

Empadinhas

Mendes

2015

DNA and Cell Biology

View full text Add to dashboard Cite

show abstract

“…Simvastatin was previously shown to enhance autophagy in osteoblastic cells and coronary arterial myocytes (14,17). The present study determined whether simvastatin elevated ox-LDL-induced autophagy in macrophages.…”

Section: Simvastatin Enhances Ox-ldl-induced Macrophage Autophagymentioning

confidence: 81%

“…Simvastatin is a widely used statin, that exhibits lipid and non-lipid effects (12,13). Recently, simvastatin was shown to enhance autophagy in coronary arterial myocytes, through inhibition of the Rac1-mammalian target of rapamycin (mTOR) signaling pathway (14). However, the effects of simvastatin on macrophage autophagy remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Simvastatin enhances oxidized-low density lipoprotein-induced macrophage autophagy and attenuates lipid aggregation

Huang

Jin

Yan

et al. 2014

Molecular Medicine Reports

View full text Add to dashboard Cite

Abstract. Macrophage autophagy exerts a protective effect in advanced atherosclerosis. It has previously been reported that oxidized low-density lipoprotein (ox-LDL) induces autophagy in endothelial cells, and simvastatin enhances autophagy in coronary arterial myocytes. However, it is currently unknown whether ox-LDL induces autophagy in macrophages, or whether simvastatin affects macrophage autophagy in atherosclerosis. The present study demonstrated that ox-LDL induced lipid accumulation in the J774A.1 macrophage cell line, in a dose-dependent manner, as determined by oil red O staining. Ox-LDL also induced autophagy in the J774A.1 cells, by converting microtubule-associated protein 1 light chain 3 (LC3) I to LC3 II, which is a well-known autophagy marker. Notably, treatment of the cells with simvastatin elevated ox-LDL-induced macrophage autophagy, this was detected through the conversion of LC3 I to LC3 II and the increased expression of Beclin1, another autophagy marker. Furthermore, it was shown that stimulation with ox-LDL led to the redistribution of green fluorescent protein (GFP)-LC3 from diffusion distribution, to the formation of puncta in the J774A.1 cells. Simvastatin promoted the ox-LDL-induced formation of GFP-LC3 puncta, as detected by confocal laser scanning microscopy. Simvastatin was also shown to inhibit ox-LDL-induced cholesterol accumulation in the J774A.1 cells, as observed by oil red O staining and CHOD-PAP assay. These results suggest that simvastatin may enhance ox-LDL-induced macrophage autophagy and attenuate lipid aggregation. IntroductionActivation, dysfunction and structural alterations of the arterial endothelium results in the subendothelial retention of oxidized low-density lipoprotein (ox-LDL) from the plasma, thereby promoting the development and progression of atherosclerosis (1). Activated endothelial cells secrete chemokines, and subsequently express adhesion molecules, which may facilitate the recruitment of leukocytes, from the blood into the arterial wall (2). Of the leukocytes, monocytes are a critical cell type that contribute to the formation of atherosclerotic plaques. In the intima, migrated monocytes differentiate into macrophages, which engulf ox-LDL to form cholesterol-laden foam cells (3).Autophagy is a conserved catabolic process in which cytoplasmic material is delivered to the lysosomal machinery for degradation and recycling. It is well-known that autophagy occurs in advanced atherosclerotic plaques (4-6), and that macrophage autophagy exerts a protective effect in advanced atherosclerosis (7). Previous studies have shown that ox-LDL may induce autophagy in endothelial cells, leading to the degradation of ox-LDL through autolysosomes (8,9). However, little is currently known about whether ox-LDL may induce autophagy in macrophages.Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. Statins impede cholesterol biosynthesis, therefore reducing blood cholesterol levels. As well as lowering lipid levels, statins have been demons...

show abstract

“…Immunoblotting was performed as previously described (2,(29)(30)(31)(32)(33)(34). Briefly, ovaries from different experimental groups were sonicated in lysis buffer containing a protease inhibitor cocktail (Sigma-Aldrich, St. Louis, MO, USA).…”

Section: Methodsmentioning

confidence: 99%

Effect of high-fat diet-induced obesity on the Akt/FoxO/Smad signaling pathway and the follicular development of the mouse ovary

Zhang

Liao

et al. 2016

Molecular Medicine Reports

View full text Add to dashboard Cite

Abstract. Obesity has a negative effect on ovarian functions, which is reported to increase the risk of infertility. The mechanism underlying obesity-induced infertility is not yet clear. The present study established a high-fat diet (HFD)-induced obesity mouse model to elucidate the mechanisms underlying the effect of HFD-induced obesity on follicular development in the mouse ovary. The 4-week-old female mice were fed with HFD or normal control (NC) diet for 15 or 20 weeks. Body mass index was used to demonstrate that the mice were obese following HFD treatment. The follicular development of the ovaries from the HFD group mice was retarded in a time-dependent manner, as demonstrated by morphological and histological examination of the ovaries. Further investigation via western blot analysis demonstrated that the activity of the transcription factor, forkhead box O3a (FoxO3a), was increased by HFD through downregulated FoxO3a phosphorylation, which may contribute to the inhibited development of ovarian follicles. To determine the regulatory mechanism of FoxO3 on the follicular development, the expression levels of FoxO3a target protein, Smad1/5/8, were also determined and there was significant decrease in phosphorylated Smad1/5/8 in the ovaries from the HFD group compared with the NC group, indicating that FoxO3a/Smad1/5/8 may be important in the regulation of follicular development. The expression levels of the upstream regulator of FoxO3a, Akt, were also examined and it was demonstrated that Akt phosphorylation was significantly reduced in the HFD group compared with the NC group, indicating that Akt/FoxO3a may be also involved in follicular development. Together, the experiments demonstrated that HFD-induced obesity affected the activity of the Akt/FoxO3a/Smad1/5/8 signaling pathway in a time-dependent manner during the follicular development of the mouse ovary, leading to abnormal follicular development. These findings may provide part of a theoretical basis for the clinical prevention and treatment of obesity-associated female infertility.

show abstract

Enhancement of Autophagy by Simvastatin through Inhibition of Rac1-mTOR Signaling Pathway in Coronary Arterial Myocytes

Cited by 119 publications

References 46 publications

Autophagy in the Fight Against Tuberculosis

Autophagy in the Fight Against Tuberculosis

Simvastatin enhances oxidized-low density lipoprotein-induced macrophage autophagy and attenuates lipid aggregation

Effect of high-fat diet-induced obesity on the Akt/FoxO/Smad signaling pathway and the follicular development of the mouse ovary

Contact Info

Product

Resources

About