Hemodynamic Shear Stress <i>via</i> ROS Modulates PCSK9 Expression in Human Vascular Endothelial and Smooth Muscle Cells and Along the Mouse Aorta

Ding, Zufeng; Liu, Shijie; Wang, Xianwei; Deng, Xiaoyan; Fan, Yubo; Sun, Changqing; Wang, Yannian; Mehta, Jawahar L.

doi:10.1089/ars.2014.6054

Cited by 180 publications

(221 citation statements)

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“…Although the major source of PCSK9 is the liver, in a recent experimental study in mice and explanted human hearts, Ding et al reported that PCSK9 is up‐regulated in the zone bordering the infarct area and determines, at least in part, infarct size, cardiac function, and autophagy . The same group reported that PCSK9 is highly expressed in vascular smooth muscle cells, and its expression and development of autophagy are regulated by well‐known inflammation mediators, such as lipopolysaccharide, tumour necrosis factor α (TNFα), and reactive oxygen species …”

Section: Discussionmentioning

confidence: 99%

Role of PCSK9 in the course of ejection fraction change after ST‐segment elevation myocardial infarction: a pilot study

et al. 2020

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Aims Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a therapeutic target for reducing plasma low‐density lipoprotein cholesterol. Beyond lipid control, recent findings suggest a deleterious effect of this protein in the pathogenesis of postmyocardial infarction left ventricle remodelling and heart failure‐related complications. The aim of this study was to assess the relationship between circulating PCSK9 and 6 month cardiac magnetic resonance imaging‐derived left ventricular ejection fraction (LVEF) after a first ST‐segment elevation myocardial infarction (STEMI). Methods and results We prospectively evaluated 40 patients with a first STEMI, LVEF < 50% and treated with primary percutaneous coronary intervention in which PCSK9 was measured 24 h postreperfusion. All patients underwent cardiac magnetic resonance imaging 1 week and 6 months after STEMI. Baseline characteristics were compared across median values of PCSK9. The association between PCSK9 levels and LVEF at 6 months was evaluated by analysis of covariance. The mean age of the sample was 60 ± 12 years and 33 (82.5%) were male patients. The infarct location was anterior in 27 patients (67.5%), and 9 patients (22.5%) were Killip class ≥ II. The mean 1 week and 6 month LVEF were 41 ± 7% and 48 ± 10%, respectively. The mean PCSK9 was 1.93 ± 0.38 U/mL. Testing the association between serum PCSK9 and 6 month LVEF with analysis of covariance revealed an inverse relationship (r = −0.35, P = 0.028). After multivariate adjustment, circulating PCSK9 remained significant and inversely associated with 6 month LVEF (P = 0.002). Conclusions In patients with a first STEMI with reduced ejection fraction at index admission and treated with primary percutaneous coronary intervention, circulating PCSK9 was associated with lower LVEF at 6 months.

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Section: Discussionmentioning

confidence: 99%

Role of PCSK9 in the course of ejection fraction change after ST‐segment elevation myocardial infarction: a pilot study

et al. 2020

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“…It was also suggested that PCSK9 enzyme function is associated with exacerbated inflammatory response in hypercholesterolemia, and atherogenesis. Ding et al (, ) observed a positive interaction between PCSK9 and Lectin‐like ox‐LDL receptor‐1 (LOX‐1), both involved in inflammation, which has important implications in several chronic inflammatory diseases. Pre‐inflammatory factors like lipopolysaccharide (LPS), inflammatory cytokines, tumor necrosis factor‐α, and ox‐LDL proportionately induce PCSK9 expression through reactive oxygen species (ROS) and nuclear factor κB activation in vascular smooth muscle cells (SMCs), and endothelial cells (ECs).…”

Section: Role Of Pcsk9 In Lipid Metabolismmentioning

confidence: 99%

PCSK9 and infection: A potentially useful or dangerous association?

Khademi

Momtazi‐Borojeni

Reiner

et al. 2017

Journal Cellular Physiology

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Elevated plasma low-density lipoprotein-cholesterol (LDL-C) concentration is the most important risk factor for atherosclerotic cardiovascular diseases (CVDs). Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a ubiquitously expressed serine proteinase which plays a key role in cholesterol metabolism, but has been found to be implicated in some other lipid-independent physiological processes. In this review, the role of PCSK9 was evaluated not only concerning lipid metabolism but also hepatitis C virus (HCV) infection, bacterial infections/sepsis, and septic shock. Collected data from clinical trials revealed that treatment with PCSK9 inhibitors has beneficial effects in lowering LDL-C via inhibition of LDL-receptors (LDL-R), an antiviral effect on HCV infection via down-regulating the surface expression of LDL-R and CD81 on hepatic cells, and a positive association with increased inflammatory responses, as well as with septic shock by down-regulation of hepatocyte LDL-R. On the other hand, PCSK9 inhibition by therapeutic fully humanized antibodies has positive effects in reducing elevated LDL-C. However, their safety and tolerability is an important issue which has to be taken into consideration.

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“…Because ECs display low permeability to plasma proteins, it has been suggested that the low across the artery wall may cause concentration polarization of LDL with the LDL increasing in concentration from bulk value towards interface within the arterial system [18]. The mass transport phenomenon of concentration polarization of LDL has been con irmed both theoretically and experimentally [19]. In the present study, we hypothesized that concentration polarization of ox-LDLs might occur leading to enhanced ox-LDL uptake by the arterial wall.…”

Section: Discussionmentioning

confidence: 99%

“…Deng et al [18] have predicted a mass transport phenomenon of c oncentration polarization of atherogenic LDLs and veri ied it experimentally in vitro [19]. The phenomenon of LDL concentration polarization could be the basis of 'residence time' and the deposition of atherogenic particles.…”

Section: Introductionmentioning

confidence: 94%

Concentration Polarization of Ox-LDL and Its Effect on Cell Proliferation and Apoptosis in Human Endothelial Cells

Ding¹

2016

J Cardiol Cardiovasc Med

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Background: Flow-dependent concentration polarization of native LDL is important in the localization of atherogenesis. However, ox-LDL plays a more important role than n-LDL in atherogenesis by inducing cell proliferation and apoptosis. We hypothesized that concentration polarization of ox-LDL may adversely affect vascular beds due to its toxicity to endothelial cell (EC) lining. Methods:Using a parallel-plate fl ow chamber technique, we studied water fi ltration rate and wall concentration of ox-LDLs EC monolayers cultured on permeable or non-permeable membranes. ECs cultured on permeable and non-permeable membranes were examined in terms of cell viability, ox-LDL uptake, LOX-1 expression and cell apoptosis (Cytochrome c and Bcl-2 expression). We observed that the wall concentration of ox-LDL was about 16% higher in the permeable group than in the permeable group (P<0.05). Cell proliferation (MTT assay) increased in response to low concentration of ox-LDL (1-5 μg/ml), and fell drastically in response to higher concentration; all these changes were more pronounced in the permeable group than in the nonpermeable group. The uptake of ox-LDL and LOX-1 expression by ECs were also signifi cantly higher in the permeable group than in the non-permeable group of cultured cells. Conclusion:These observations suggest that concentration polarization of ox-LDL occurs in an artery that is permeable to water, and ox-LDL concentration polarization can enhance ox-LDL accumulation into the arterial wall and accelerate EC proliferation at low concentrations and apoptosis at high concentrations, possibly via LOX-1 expression.

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Hemodynamic Shear Stress via ROS Modulates PCSK9 Expression in Human Vascular Endothelial and Smooth Muscle Cells and Along the Mouse Aorta

Cited by 180 publications

References 49 publications

Role of PCSK9 in the course of ejection fraction change after ST‐segment elevation myocardial infarction: a pilot study

Role of PCSK9 in the course of ejection fraction change after ST‐segment elevation myocardial infarction: a pilot study

PCSK9 and infection: A potentially useful or dangerous association?

Concentration Polarization of Ox-LDL and Its Effect on Cell Proliferation and Apoptosis in Human Endothelial Cells

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