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Zhen Tian - One of the best experts on this subject based on the ideXlab platform.
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sonodynamic therapy induced Foam Cells apoptosis activates the phagocytic pparγ lxrα abca1 abcg1 pathway and promotes cholesterol efflux in advanced plaque
Theranostics, 2018Co-Authors: Huan Wang, Yang Yang, Xin Sun, Fang Tian, Shuyuan Guo, Wei Wang, Zhen TianAbstract:In advanced atherosclerotic plaques, defective efferocytosis of apoptotic Foam Cells and decreased cholesterol efflux contribute to lesion progression. In our previous study, we demonstrated that 5-aminolevulinic acid (ALA)-mediated sonodynamic therapy (SDT) could induce Foam Cells apoptosis via the mitochondrial-caspase pathway. In the current research, we sought to explore ALA-SDT-induced apoptosis of phagocytes and the effects of cholesterol efflux and efferocytosis in advanced apoE-/- mice plaque. Methods: apoE-/- mice fed western diet were treated with ALA-SDT and sacrificed at day 1, day 3, day 7 and day 28 post treatment. THP-1 macrophage-derived Foam Cells were treated with ALA-SDT. 5 hours later, the supernatant was collected and added to fresh Foam Cells (phagocytes). Then, the lipid area, efferocytosis, cholesterol efflux, anti-inflammatory reactions and PPARγ-LXRα-ABCA1/ABCG1 pathway were detected in plaque in vivo and in phagocytes in vitro. Results: We found that ALA-SDT induced Foam Cells apoptosis coupled with efferocytosis and upregulation of Mer tyrosine kinase (MerTK) both in vivo and in vitro. The lipid content in plaque decreased as early as 1 day after ALA-SDT and this tendency persisted until 28 days. The enhancement of phagocytes cholesterol efflux was accompanied by an approximately 40% decrease in free cholesterol and a 24% decrease in total cholesterol in vitro. More importantly, anti-inflammatory factors such as TGFβ and IL-10 were upregulated by ALA-SDT treatment. Finally, we found that PPARγ-LXRα-ABCA1/ABCG1 pathway was activated both in vivo and in vitro by ALA-SDT, which could be blocked by PPARγ siRNA. Conclusions: Activation of PPARγ-LXRα-ABCA1/ABCG1 pathway induced by ALA-SDT treatment engages a virtuous cycle that enhances efferocytosis, cholesterol efflux and anti-inflammatory reactions in advanced plaque in vivo and in phagocytes in vitro.
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5 aminolevulinic acid mediated sonodynamic therapy inhibits ripk1 ripk3 dependent necroptosis in thp 1 derived Foam Cells
Scientific Reports, 2016Co-Authors: Fang Tian, Wei Wang, Zhen Tian, Zengxiang Dong, Bicheng Li, Peng Shan, Haiyang Wang, Jiali Cheng, Zhiguo Zhang, Ye TianAbstract:Necroptosis, or programmed necrosis, contributes to the formation of necrotic cores in atherosclerotic plaque in animal models. However, whether inhibition of necroptosis ameliorates atherosclerosis is largely unknown. In this study, we demonstrated that necroptosis occurred in clinical atherosclerotic samples, suggesting that it may also play an important role in human atherosclerosis. We established an in vitro necroptotic model in which necroptosis was induced in THP-1-derived Foam Cells by serum deprivation. With this model, we demonstrated that 5-aminolevulinic acid-mediated sonodynamic therapy (ALA-SDT) inhibited necroptosis while promoting apoptosis. ALA-SDT activated the caspase-3 and caspase-8 pathways in Foam Cells, which is responsible for the switch from necroptosis to apoptosis. The inhibition of either caspase-8 or caspase-3 abolished the anti-necroptotic effect of ALA-SDT. In addition, we found that caspase-3 activation peaked 4 hours after ALA-SDT treatment, 2 hours earlier than maximal caspase-8activation. Taken together, our data indicate that ALA-SDT mediates the switch from necroptosis to apoptosis by activating the caspase-3 and caspase-8 pathways and may improve the prognosis of atherosclerosis.
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the predominant pathway of apoptosis in thp 1 macrophage derived Foam Cells induced by 5 aminolevulinic acid mediated sonodynamic therapy is the mitochondria caspase pathway despite the participation of endoplasmic reticulum stress
Cellular Physiology and Biochemistry, 2014Co-Authors: Huan Wang, Yang Yang, Xin Sun, Shuyuan Guo, Wei Wang, Jiali Cheng, Haibo Chen, Juhua Dan, Li Peng, Zhen TianAbstract:Background: In advanced atherosclerosis, chronic endoplasmic reticulum (ER) stress induces Foam Cells apoptosis and generates inflammatory reactions. Methods: THP-1 macrophage-derived Foam Cells (FC) were incubated with 1 mM 5-aminolevulinic acid (ALA). After ALA mediated sonodynamic therapy (ALA-SDT), apoptosis of FC was assayed by Annexin V-PI staining. Intracellular reactive oxygen species (ROS) and mitochondrial membrane potential were detected by staining with CellROX® Green Reagent and jc-1. Pretreatment of FC with N-acetylcysteine (NAC), Z-VAD-FMK or 4-phenylbutyrate (4-PBA), mitochondria apoptotic pathway associated proteins and C/EBP-homologous (CHOP) expressions were assayed by wertern blotting. Results: Burst of apoptosis of FC was observed at 5-hour after ALA-SDT with 6-hour incubation of ALA and 0.4 W/cm2 ultrasound. After ALA-SDT, intracellular ROS level increased and mitochondrial membrane potential collapsed. Translocations of cytochrome c from mitochondria into cytosol and Bax from cytosol into mitochondria, cleaved caspase 9, cleaved caspase 3, upregulation of CHOP, as well as downregulation of Bcl-2 after ALA-SDT were detected, which could be suppressed by NAC. Activation of mitochondria-caspase pathway could not be inhibited by 4-PBA. Cleaved caspase 9 and caspase 3 as well as apoptosis induced by ALA-SDT could be inhibited by Z-VAD-FMK. Conclusion: The mitochondria-caspase pathway is predominant in the apoptosis of FC induced by ALA-SDT though ER stress participates in.
Chaoke Tang - One of the best experts on this subject based on the ideXlab platform.
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Foam Cells in atherosclerosis
Clinica Chimica Acta, 2013Co-Authors: Dawei Zhang, Kai Yin, Chaoke TangAbstract:Atherosclerosis is a chronic disease characterized by the deposition of excessive cholesterol in the arterial intima. Macrophage Foam Cells play a critical role in the occurrence and development of atherosclerosis. The generation of these Cells is associated with imbalance of cholesterol influx, esterification and efflux. CD36 and scavenger receptor class A (SR-A) are mainly responsible for uptake of lipoprotein-derived cholesterol by macrophages. Acyl coenzyme A:cholesterol acyltransferase-1 (ACAT1) and neutral cholesteryl ester hydrolase (nCEH) regulate cholesterol esterification. ATP-binding cassette transporters A1(ABCA1), ABCG1 and scavenger receptor BI (SR-BI) play crucial roles in macrophage cholesterol export. When inflow and esterification of cholesterol increase and/or its outflow decrease, the macrophages are ultimately transformed into lipid-laden Foam Cells, the prototypical Cells in the atherosclerotic plaque. The aim of this review is to describe what is known about the mechanisms of cholesterol uptake, esterification and release in macrophages. An increased understanding of the process of macrophage Foam cell formation will help to develop novel therapeutic interventions for atherosclerosis.
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apelin 13 increases expression of atp binding cassette transporter a1 via activating protein kinase c α signaling in thp 1 macrophage derived Foam Cells
Atherosclerosis, 2013Co-Authors: Xiaoyan Liu, Dawei Zhang, Shilin Tang, Guojun Zhao, Xinping Ouyang, Yanyan Tang, Haijun Kuang, Chaoke TangAbstract:Apelin has an antiatherogenic function through activating protein kinase C (PKC) to initiate a series of cellular signaling pathways. PKC phosphorylates and stabilizes ATP-binding cassette transporter A1 (ABCA1) through inhibiting its degradation mediated by calpain. Thus, in the present study, we investigated whether apelin-13 affects expression of ABCA1 through PKC signaling. The results showed that apelin-13 dramatically increased cholesterol efflux from THP-1 macrophage-derived Foam Cells and reduced cellular cholesterol levels. ABCA1 protein but not mRNA levels were dramatically increased by apelin-13, and calpain-induced degradation of ABCA1 and calpain activity were suppressed with treatment of apelin-13. However, the effects of apelin-13 on ABCA1 protein expression, cellular cholesterol efflux and calpain activity were abolished by depletion of PKCα, suggesting the potential important role of PKCα. In addition, apelin-13 was shown to phosphorylate serine residues in ABCA1 through the PKCα pathway. Thus, apelin-13 appears to activate PKCα, phosphorylate ABCA1 and inhibit calpain-mediated proteolysis, thereby promoting cholesterol efflux and reducing Foam cell formation. Our study herein described a possible mechanism for understanding the antiatherogenic effects of apelin on attenuating the progression of atherosclerosis.
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interleukin 18 and interleukin 12 together downregulate atp binding cassette transporter a1 expression through the interleukin 18r nuclear factor κb signaling pathway in thp 1 macrophage derived Foam Cells
Circulation, 2012Co-Authors: Hailu Jiang, Dawei Zhang, Kai Yin, Guojun Zhao, Xinping Ouyang, Wujun Chen, Zhisheng Jiang, Chaoke TangAbstract:Background: Interleukin (IL)-18 and IL-12 synergize for the production of interferon (IFN)-γ, which can downregulate ATP-binding cassette transporter A1 (ABCA1) expression. The aim of the present study was to investigate the effect of IL-18 and/or IL-12 on ABCA1 expression. Methods and Results: IL-18 combined with IL-12 decreased ABCA1 expression and cellular cholesterol efflux in THP-1 macrophage-derived Foam Cells, whereas IL-18 or IL-12 alone had no effect. IL-12 increased IL-18 receptor (IL-18R) expression, which was suppressed by small interfering RNA (siRNA) for signal transducer and activator of transcription 3. IL-18R but not IL-12 receptor siRNA completely reversed the effects of IL-18 and IL-12 on ABCA1 expression and cellular cholesterol efflux. Treatment with IL-18 plus IL-12 markedly augmented nuclear translocation of nuclear factor (NF)-κB but had no effect on expression and activity of liver X receptor α. IL-18 and IL-12 also significantly increased zinc finger protein 202 (ZNF202) levels and IFN-γ secretion. Furthermore, siRNA for ZNF202 or IFN-γ significantly impaired IL-18/IL-12-induced suppression of ABCA1, whereas NF-κB siRNA treatment blocked IL-18/IL-12' action on ZNF202 levels, IFN-γ secretion, and ABCA1 expression. Conclusions: IL-18 and IL-12 together can decrease ABCA1 expression and cellular cholesterol efflux in THP-1 macrophage-derived Foam Cells through the IL-18R/NF-κB signaling pathway. (Circ J 2012; 76: 1780–1791)
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tgf β1 up regulates expression of abca1 abcg1 and sr bi through liver x receptor α signaling pathway in thp 1 macrophage derived Foam Cells
Journal of Atherosclerosis and Thrombosis, 2010Co-Authors: Qian Wang, Xiehong Liu, Ji Xiao, Duanfang Liao, Jim Xiang, Chaoke TangAbstract:Aim High density lipoprotein (HDL) and its apolipoproteins can promote cholesterol efflux from macrophage Foam Cells via the ATP-binding cassette transporter A1 (ABCA1), ABCG1, and scavenger receptor class B type I (SR-BI). Liver X receptors (LXRs) operate as cholesterol sensors which may protect from cholesterol overload by stimulating cholesterol efflux from Cells to HDL through ABCA1, ABCG1 and SR-BI. The regulation of ABCA1, ABCG1 and SR-BI expression by cytokines present within the microenvironment of the atheroma may play an important role in determining the impact of reverse cholesterol transport on the atherosclerotic lesion. In the current study, we examined the effect of transforming growth factor-beta1 (TGF-beta1) on expressions of ABCA1, ABCG1 and SR-BI and explored the role of LXR alpha in the regulation of ABCA1, ABCG1 and SR-BI in THP-1 macrophage-derived Foam Cells. Methods and results TGF-beta1 significantly increased expressions of ABCA1, ABCG1 and SR-BI at both transcriptional and translational levels in a dose-dependent and time-dependent manner. Cellular cholesterol content was decreased while cholesterol efflux was increased by TGF-beta1 treatment. Moreover, LXR alpha was up-regulated by TGF-beta1 treatment. In addition, LXR alpha small interfering RNA completely abolished the promotion effect induced by TGF-beta1. Conclusion These results provide evidence that TGF-beta1 up-regulates expressions of ABCA1, ABCG1 and SR-BI through the LXR alpha pathway in THP-1 macrophage-derived Foam Cells.
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eicosapentaenoic acid reduces abca1 serine phosphorylation and impairs abca1 dependent cholesterol efflux through cyclic amp protein kinase a signaling pathway in thp 1 macrophage derived Foam Cells
Atherosclerosis, 2009Co-Authors: Xiehong Liu, Ji Xiao, Duanfang Liao, Jim Xiang, Chaoke TangAbstract:ABCA1 is a key mediator of cholesterol efflux to apoA-I in cholesterol loaded macrophages, a first step of RCT in vivo. Unsaturated fatty acids can inhibit cholesterol efflux from macrophages by increasing degradation of ABCA1. However, the detailed mechanisms of ABCA1 regulation by unsaturated fatty acids are not fully understood. In the present study, we investigated the effects of EPA on ABCA1 expression and ABCA1-dependent cholesterol efflux and examined the role of cAMP/PKA pathway on the regulation of ABCA1 by EPA in THP-1 macrophage-derived Foam Cells. Results showed that EPA significantly destabilized ABCA1 protein and reduced ABCA1-dependent cholesterol efflux but had no effect on ABCA1 mRNA expression. We also revealed that EPA markedly reduced cAMP level and PKA activity and ABCA1 serine phosphorylation. PKA-specific activation by PKA agonist markedly compensated the down-regulation of ABCA1 serine phosphorylation and ABCA1-mediated cholesterol efflux by EPA, while, siRNA of PKA leaded to reduce of ABCA1 serine phosphorylation and ABCA1-mediated cholesterol efflux more significantly than EPA. However, EPA-Induced enhancement of degradation rate of ABCA1 protein did not change by treatment with PKA agonist or PKA-siRNA. These results provide evidence that EPA may have dual negative effects on ABCA1 activity by decreasing ABCA1 protein level and by reducing PKA-mediated ABCA1 serine phosphorylation in THP-1 macrophage-derived Foam Cells.
Robin P Choudhury - One of the best experts on this subject based on the ideXlab platform.
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nicotinic acid receptor gpr109a is down regulated in human macrophage derived Foam Cells
PLOS ONE, 2013Co-Authors: Joshua T Chai, Janet E Digby, Neil Ruparelia, Andrew Jefferson, Ashok Handa, Robin P ChoudhuryAbstract:Nicotinic acid (NA) regresses atherosclerosis in human imaging studies and reduces atherosclerosis in mice, mediated by myeloid Cells, independent of lipoproteins. Since GPR109A is expressed by human monocytes, we hypothesized that NA may drive cholesterol efflux from Foam Cells. In THP-1 Cells NA suppressed LPS-induced mRNA transcription of MCP-1 by 76.6±12.2% (P<0.01) and TNFα by 56.1±11.5% (P<0.01), yet restored LPS-induced suppression of PPARγ transcription by 536.5±46.4% (P<0.001) and its downstream effector CD36 by 116.8±19.8% (P<0.01). Whilst direct PPARγ-agonism promoted cholesterol efflux from THP-1 derived Foam Cells by 37.7±3.1% (P<0.01) and stimulated transcription of LXRα by 87.9±9.5% (P<0.001) and ABCG1 by 101.2±15.5% (P<0.01), NA showed no effect in Foam Cells on either cholesterol efflux or key RCT genes transcription. Upon Foam cell induction, NA lost its effect on PPARγ and cAMP pathways, since its receptor, GPR109A, was down-regulated by Foam cell transformation. This observation was confirmed in explanted human carotid plaques. In conclusion, despite NA’s anti-inflammatory effect on human macrophages, it has no effect on Foam Cells in reverse cholesterol transport; due to GPR109A down-regulation.
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nicotinic acid receptor gpr109a is down regulated in human macrophage derived Foam Cells
Heart, 2013Co-Authors: Joshua T Chai, Janet E Digby, Neil Ruparelia, Andrew Jefferson, Ashok Handa, Robin P ChoudhuryAbstract:Introduction Nicotinic acid (NA) has been known to exert favourable effects on plasma lipoproteins. It regresses atherosclerosis in human imaging studies and reduces atherosclerosis in mice, mediated by its receptor GPR109a on myeloid Cells, independent of its lipoprotein effect. Since GPR109a is expressed by human monocytes, we hypothesized that NA may drive cholesterol efflux from human macrophage-derived Foam Cells. Methods THP-1 Cells were induced into Foam Cells by acetylated LDL. After treatment with NA, GW1929 (a PPARγ agonist) and vehicle controls, cholesterol efflux was assessed using HDL3 and apo-AI as cholesterol acceptors. qRT-PCR was performed using primers for genes responsible for inflammation and reverse cholesterol transport (RCT). ELISA9s for PPARγ activity and cAMP response were performed to investigate NA9s putative cellular mechanisms of action. Fluorescence immunohistochemistry on ex-vivo human carotid atherosclerotic plaques was carried out against CD68, adipophilin (a Foam Cells marker), as well as GPR109a. Immediately adjacent sections were stained with Oil-red-O to visualized lipid content and distribution. Results In basal THP-1 Cells, NA suppressed LPS-induced mRNA transcription of MCP-1 by 76.6±12.2% (P Conclusions This study shows that despite NA9s anti-inflammatory effect on human macrophages, it does not appear to enhance cholesterol efflux in Foam Cells, which is at least partially ascribed to GPR109a down-regulation upon Foam cell transformation. This implies that direct NA-promotion of cholesterol efflux from Foam Cells may not contribute to atherosclerosis regression, which has been demonstrated with this drug.
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mechanisms of disease macrophage derived Foam Cells emerging as therapeutic targets in atherosclerosis
Nature Reviews Cardiology, 2005Co-Authors: Robin P Choudhury, Justin M S Lee, David R GreavesAbstract:The limited efficacy of current treatment strategies for targeting atherosclerosis and its complications requires new therapeutic options to be explored. From early fatty-streak lesions to advanced plaques, macrophage-derived Foam Cells are integral to the development and progression of atherosclerosis. Elucidation of molecular and cellular processes involving macrophages has led to numerous therapeutic targets being suggested. Potential sites of intervention range from monocyte recruitment, through cholesterol uptake and esterification, to cholesterol evacuation and macrophage egress from plaque. In addition, complex patterns of transcriptional regulation of genes involved in macrophage lipid homeostasis and in the regulation of inflammation have been partly unraveled. Recognition of ATP-binding cassette cholesterol transport mechanisms and cellular interactions with cholesterol-accepting apolipoproteins (or synthetic mimetics) opens up new potential therapies to induce atherosclerosis regression in humans. This review presents a systematic evaluation of actual and potential macrophage-directed pharmacologic interventions. It reflects the timely convergence of three important strands: advances in molecular and cell biology that have suggested therapeutic targets in macrophages; the development of multiple classes of drugs targeting these pathways; and the emergence of sensitive imaging techniques that have enabled identification of changes in plaque size and composition in response to treatment.
Ye Tian - One of the best experts on this subject based on the ideXlab platform.
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upconversion nanoparticle mediated photodynamic therapy induces autophagy and cholesterol efflux of macrophage derived Foam Cells via ros generation
Cell Death and Disease, 2017Co-Authors: Xiaobo B Han, Yueqing Q Jiang, Hao Wang, Jiayuan Y Kou, Yinghong H Zheng, Zhongni Liu, Dou Dou, You Wang, Ye Tian, Liming YangAbstract:Macrophage-derived Foam Cells are a major component of atherosclerotic plaques and have an important role in the progression of atherosclerotic plaques, thus posing a great threat to human health. Photodynamic therapy (PDT) has emerged as a therapeutic strategy for atherosclerosis. Here, we investigated the effect of PDT mediated by upconversion fluorescent nanoparticles encapsulating chlorin e6 (UCNPs-Ce6) on the cholesterol efflux of THP-1 macrophage-derived Foam Cells and explored the possible mechanism of this effect. First, we found that PDT notably enhanced the cholesterol efflux and the induction of autophagy in both THP-1 and peritoneal macrophage-derived Foam Cells. The autophagy inhibitor 3-methyladenine and an ATG5 siRNA significantly attenuated PDT-induced autophagy, which subsequently suppressed the ABCA1-mediated cholesterol efflux. Furthermore, the reactive oxygen species (ROS) produced by PDT were responsible for the induction of autophagy, which could be blocked by the ROS inhibitor N-acetyl cysteine (NAC). NAC also reversed the PDT-induced suppression of p-mTOR and p-Akt. Therefore, our findings demonstrate that PDT promotes cholesterol efflux by inducing autophagy, and the autophagy was mediated in part through the ROS/PI3K/Akt/mTOR signaling pathway in THP-1 and peritoneal macrophage-derived Foam Cells.
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5 aminolevulinic acid mediated sonodynamic therapy inhibits ripk1 ripk3 dependent necroptosis in thp 1 derived Foam Cells
Scientific Reports, 2016Co-Authors: Fang Tian, Wei Wang, Zhen Tian, Zengxiang Dong, Bicheng Li, Peng Shan, Haiyang Wang, Jiali Cheng, Zhiguo Zhang, Ye TianAbstract:Necroptosis, or programmed necrosis, contributes to the formation of necrotic cores in atherosclerotic plaque in animal models. However, whether inhibition of necroptosis ameliorates atherosclerosis is largely unknown. In this study, we demonstrated that necroptosis occurred in clinical atherosclerotic samples, suggesting that it may also play an important role in human atherosclerosis. We established an in vitro necroptotic model in which necroptosis was induced in THP-1-derived Foam Cells by serum deprivation. With this model, we demonstrated that 5-aminolevulinic acid-mediated sonodynamic therapy (ALA-SDT) inhibited necroptosis while promoting apoptosis. ALA-SDT activated the caspase-3 and caspase-8 pathways in Foam Cells, which is responsible for the switch from necroptosis to apoptosis. The inhibition of either caspase-8 or caspase-3 abolished the anti-necroptotic effect of ALA-SDT. In addition, we found that caspase-3 activation peaked 4 hours after ALA-SDT treatment, 2 hours earlier than maximal caspase-8activation. Taken together, our data indicate that ALA-SDT mediates the switch from necroptosis to apoptosis by activating the caspase-3 and caspase-8 pathways and may improve the prognosis of atherosclerosis.
Wei Wang - One of the best experts on this subject based on the ideXlab platform.
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sonodynamic therapy induced Foam Cells apoptosis activates the phagocytic pparγ lxrα abca1 abcg1 pathway and promotes cholesterol efflux in advanced plaque
Theranostics, 2018Co-Authors: Huan Wang, Yang Yang, Xin Sun, Fang Tian, Shuyuan Guo, Wei Wang, Zhen TianAbstract:In advanced atherosclerotic plaques, defective efferocytosis of apoptotic Foam Cells and decreased cholesterol efflux contribute to lesion progression. In our previous study, we demonstrated that 5-aminolevulinic acid (ALA)-mediated sonodynamic therapy (SDT) could induce Foam Cells apoptosis via the mitochondrial-caspase pathway. In the current research, we sought to explore ALA-SDT-induced apoptosis of phagocytes and the effects of cholesterol efflux and efferocytosis in advanced apoE-/- mice plaque. Methods: apoE-/- mice fed western diet were treated with ALA-SDT and sacrificed at day 1, day 3, day 7 and day 28 post treatment. THP-1 macrophage-derived Foam Cells were treated with ALA-SDT. 5 hours later, the supernatant was collected and added to fresh Foam Cells (phagocytes). Then, the lipid area, efferocytosis, cholesterol efflux, anti-inflammatory reactions and PPARγ-LXRα-ABCA1/ABCG1 pathway were detected in plaque in vivo and in phagocytes in vitro. Results: We found that ALA-SDT induced Foam Cells apoptosis coupled with efferocytosis and upregulation of Mer tyrosine kinase (MerTK) both in vivo and in vitro. The lipid content in plaque decreased as early as 1 day after ALA-SDT and this tendency persisted until 28 days. The enhancement of phagocytes cholesterol efflux was accompanied by an approximately 40% decrease in free cholesterol and a 24% decrease in total cholesterol in vitro. More importantly, anti-inflammatory factors such as TGFβ and IL-10 were upregulated by ALA-SDT treatment. Finally, we found that PPARγ-LXRα-ABCA1/ABCG1 pathway was activated both in vivo and in vitro by ALA-SDT, which could be blocked by PPARγ siRNA. Conclusions: Activation of PPARγ-LXRα-ABCA1/ABCG1 pathway induced by ALA-SDT treatment engages a virtuous cycle that enhances efferocytosis, cholesterol efflux and anti-inflammatory reactions in advanced plaque in vivo and in phagocytes in vitro.
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5 aminolevulinic acid mediated sonodynamic therapy inhibits ripk1 ripk3 dependent necroptosis in thp 1 derived Foam Cells
Scientific Reports, 2016Co-Authors: Fang Tian, Wei Wang, Zhen Tian, Zengxiang Dong, Bicheng Li, Peng Shan, Haiyang Wang, Jiali Cheng, Zhiguo Zhang, Ye TianAbstract:Necroptosis, or programmed necrosis, contributes to the formation of necrotic cores in atherosclerotic plaque in animal models. However, whether inhibition of necroptosis ameliorates atherosclerosis is largely unknown. In this study, we demonstrated that necroptosis occurred in clinical atherosclerotic samples, suggesting that it may also play an important role in human atherosclerosis. We established an in vitro necroptotic model in which necroptosis was induced in THP-1-derived Foam Cells by serum deprivation. With this model, we demonstrated that 5-aminolevulinic acid-mediated sonodynamic therapy (ALA-SDT) inhibited necroptosis while promoting apoptosis. ALA-SDT activated the caspase-3 and caspase-8 pathways in Foam Cells, which is responsible for the switch from necroptosis to apoptosis. The inhibition of either caspase-8 or caspase-3 abolished the anti-necroptotic effect of ALA-SDT. In addition, we found that caspase-3 activation peaked 4 hours after ALA-SDT treatment, 2 hours earlier than maximal caspase-8activation. Taken together, our data indicate that ALA-SDT mediates the switch from necroptosis to apoptosis by activating the caspase-3 and caspase-8 pathways and may improve the prognosis of atherosclerosis.
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the predominant pathway of apoptosis in thp 1 macrophage derived Foam Cells induced by 5 aminolevulinic acid mediated sonodynamic therapy is the mitochondria caspase pathway despite the participation of endoplasmic reticulum stress
Cellular Physiology and Biochemistry, 2014Co-Authors: Huan Wang, Yang Yang, Xin Sun, Shuyuan Guo, Wei Wang, Jiali Cheng, Haibo Chen, Juhua Dan, Li Peng, Zhen TianAbstract:Background: In advanced atherosclerosis, chronic endoplasmic reticulum (ER) stress induces Foam Cells apoptosis and generates inflammatory reactions. Methods: THP-1 macrophage-derived Foam Cells (FC) were incubated with 1 mM 5-aminolevulinic acid (ALA). After ALA mediated sonodynamic therapy (ALA-SDT), apoptosis of FC was assayed by Annexin V-PI staining. Intracellular reactive oxygen species (ROS) and mitochondrial membrane potential were detected by staining with CellROX® Green Reagent and jc-1. Pretreatment of FC with N-acetylcysteine (NAC), Z-VAD-FMK or 4-phenylbutyrate (4-PBA), mitochondria apoptotic pathway associated proteins and C/EBP-homologous (CHOP) expressions were assayed by wertern blotting. Results: Burst of apoptosis of FC was observed at 5-hour after ALA-SDT with 6-hour incubation of ALA and 0.4 W/cm2 ultrasound. After ALA-SDT, intracellular ROS level increased and mitochondrial membrane potential collapsed. Translocations of cytochrome c from mitochondria into cytosol and Bax from cytosol into mitochondria, cleaved caspase 9, cleaved caspase 3, upregulation of CHOP, as well as downregulation of Bcl-2 after ALA-SDT were detected, which could be suppressed by NAC. Activation of mitochondria-caspase pathway could not be inhibited by 4-PBA. Cleaved caspase 9 and caspase 3 as well as apoptosis induced by ALA-SDT could be inhibited by Z-VAD-FMK. Conclusion: The mitochondria-caspase pathway is predominant in the apoptosis of FC induced by ALA-SDT though ER stress participates in.