PCSK9 siRNA suppresses the inflammatory response induced by oxLDL through inhibition of NF-κB activation in THP-1-derived macrophages

Tang, Zhi‐Han; Jiang, Lu; Peng, Juan; Zhong, Ren; Wei, Dangheng; Wu, Chunyang; Pan, Lihong; Jiang, Zhi‐Sheng; Liu, Lu‐Shan

doi:10.3892/ijmm.2012.1072

Cited by 164 publications

(132 citation statements)

References 35 publications

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“…The positive correlation between the PLT count and LDL-C level and multiple metabolic factors reported in population studies suggests a potential link between the PLT count and dyslipidemia 1,2) . Secondly, experimental studies have shown that lipopolysaccharide-induced inflammation stimulates the expression of PCSK9, whereas knockdown of PCSK9 mediated by small-interfering RNA (siRNA) attenuates the ox-LDL-induced expression of proinflammatory genes 20,21) . Clinically, we found that the plasma PCSK9 level seems to be independently associated with traditional markers of chronic low-grade inflammation 7) .…”

Section: Discussionmentioning

confidence: 99%

The Relationship between the Plasma PCSK9 Levels and Platelet Indices in Patients with Stable Coronary Artery Disease

Zhu

Guo

et al. 2015

JAT

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Aim: Recent studies have shown that platelet indices are linked to metabolic and cardiovascular diseases, in addition to being markers of hemostasis. These studies suggested that they could be modified by various biomolecules, including lipids. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a newly-identified member, plays a key role in lipid metabolism and atherosclerosis. Therefore, we evaluated the relationship between the plasma PCSK9 level and platelet indices.

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Section: Discussionmentioning

confidence: 99%

The Relationship between the Plasma PCSK9 Levels and Platelet Indices in Patients with Stable Coronary Artery Disease

Zhu

Guo

et al. 2015

JAT

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“…Nuclear factor-κB (NF-κB) is a transcription factor that has crucial roles in inflammation, immunity, cell proliferation and apoptosis (4)(5)(6). Activation of NF-κB is controlled by the inhibitor of κB (I-κB), which retains NF-κB in the cytoplasm (7).…”

Section: Introductionmentioning

confidence: 99%

Propofol selectively inhibits nuclear factor-κB activity by suppressing p38 mitogen-activated protein kinase signaling in human EA.hy926 endothelial cells during intermittent hypoxia/reoxygenation

Zhang

2014

Molecular Medicine Reports

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Abstract. Intermittent hypoxia/reoxygenation (IHR) induces proinflammatory cytokines, contributing to the pathogenic process of atherosclerosis associated with obstructive sleep apnea (OSA). Two transcription factors, nuclear factor-κB (NF-κB) and hypoxia-inducible factor-1 (HIF-1), have been indicated to mediate proinflammatory cytokines during IHR. The anti-inflammatory effects of propofol have attracted increasing attention in regard to the treament of multiple diseases associated with inflammation. The present study examined whether propofol inhibits NF-κB and HIF-1 activity in vascular endothelial cells during IHR. EA.hy926 endothelial cells were exposed to IHR for 64 cycles with or without propofol treatment. Gene knockdown by transfection of siRNA against p38 mitogen-activated protein kinase (MAPK) was also used to investigate the molecular mechanisms. Compared with the control group, IHR exposure significantly induced the activation of NF-κB and HIF-1, enhanced the mRNA expression of proinflammatory cytokines and increased the activation of p38 MAPK. Propofol dose-dependently inhibited the IHR-induced activation of NF-κB, but did not change the activation of HIF-1, which was accompanied by decreased levels of proinflammatory cytokines. In addition, IHR-induced p38 MAPK activity was attenuated by propofol in a similar manner to the reduction in NF-κB activity. Furthermore, knockdown of p38 MAPK with siRNA significantly reduced the IHR-induced activation of NF-κB, while not affecting HIF-1. These data demonstrate that propofol selectively attenuates the IHR-induced activation of NF-κB, but not HIF-1, in vascular endothelial cells, and these beneficial effects are likely to be based on the inhibition of the p38 MAPK signaling pathway. Propofol may have the potential to prevent atherosclerosis in patients with OSA by inhibiting NF-κB-mediated inflammation in the vascular endothelium.

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“…Experimental data show that PCSK9 is markedly induced by diverse inflammatory stimuli, such as lipopolysaccharides, zymosan, and turpentine 33) , resulting in a significant increase in LDL-C levels. Importantly, oxidized LDL (oxLDL), a major proinflammatory factor in the development of atherosclerosis, also increases PCSK9 expression by altering the secretion of inflammatory chemokines, such as interleukin-1 (IL-1 ), IL-6, and tumor necrosis factor-, in THP-1-derived macrophages in a dose-dependent manner 34) . Furthermore, siRNA-mediated knockdown of PCSK9 suppresses oxLDL-induced proinflammatory chemokine synthesis and secretion by inhibiting nuclear factor kappa B alpha degradation and nuclear factor kappa B translocation, which have an anti-inflammatory role in macrophages 34) .…”

Section: Pcsk9 and Inflammationmentioning

confidence: 99%

“…Importantly, oxidized LDL (oxLDL), a major proinflammatory factor in the development of atherosclerosis, also increases PCSK9 expression by altering the secretion of inflammatory chemokines, such as interleukin-1 (IL-1 ), IL-6, and tumor necrosis factor-, in THP-1-derived macrophages in a dose-dependent manner 34) . Furthermore, siRNA-mediated knockdown of PCSK9 suppresses oxLDL-induced proinflammatory chemokine synthesis and secretion by inhibiting nuclear factor kappa B alpha degradation and nuclear factor kappa B translocation, which have an anti-inflammatory role in macrophages 34) . In our clinical study, we reportedthat plasma PCSK9 levels are associated with traditional markers of chronic low-grade inflammation, which are known CAD risk factors, such as circulating white blood cell count and platelet count 13,35) .…”

Section: Pcsk9 and Inflammationmentioning

confidence: 99%

PCSK9: A key factor modulating atherosclerosis

2015

JAT

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Coronary artery disease (CAD) due to obstructive atherosclerosis is a leading cause of death and has been recognized as a worldwide health threat. Measures to decrease low-density lipoprotein cholesterol (LDL-C) levels are the cornerstone in the management of patients with atherosclerotic cardiovascular disease, particularly those with CAD, for over two decades. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a newly recognized protein, plays a key role in cholesterol homeostasis by enhancing degradation of hepatic LDL receptor (LDLR). Interestingly, PCSK9 is also involved in the inflammatory process. Plasma PCSK9 and lipid or nonlipid cardiovascular risk factors are correlated, and the associations between PCSK9 with cardiovascular health and disease make this protein worthy of attention for the treatment of hyperlipidemia and atherosclerosis. Here, we provide an overview of the physiological role of PCSK9, which contributes to atherosclerosis, and provide data on PCSK9 as a novel pharmacological target. Clinical evidence shows that PCSK9 inhibition is as promising as statins as a target to treat CAD. The efficacy of these drugs may potentially enable effective CAD prophylaxis for more patients.

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PCSK9 siRNA suppresses the inflammatory response induced by oxLDL through inhibition of NF-κB activation in THP-1-derived macrophages

Cited by 164 publications

References 35 publications

The Relationship between the Plasma PCSK9 Levels and Platelet Indices in Patients with Stable Coronary Artery Disease

The Relationship between the Plasma PCSK9 Levels and Platelet Indices in Patients with Stable Coronary Artery Disease

Propofol selectively inhibits nuclear factor-κB activity by suppressing p38 mitogen-activated protein kinase signaling in human EA.hy926 endothelial cells during intermittent hypoxia/reoxygenation

PCSK9: A key factor modulating atherosclerosis

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