scholarly journals Proprotein convertase subtilisin/kexin type 9 links inflammation to vascular endothelial cell dysfunction

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
T Leucker ◽  
N Amat-Codina ◽  
S Chelko ◽  
G Gerstenblith
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cell ◽  
Vascular Endothelial Cell ◽  
Clinical Manifestations ◽  
Fold Increase ◽  
Atherosclerotic Cardiovascular Disease ◽  
Vascular Endothelial ◽  
Proprotein Convertase ◽  
Necrosis Factor Alpha ◽  
No Bioavailability

Abstract   Vascular endothelial cell (EC) dysfunction is a pathological mediator of the development, progression, and clinical manifestations of atherosclerotic disease. Inflammation is associated with EC dysfunction, but the responsible mechanisms are not well characterized. There is substantial evidence that serum proprotein convertase subtilisin/kexin type 9 (PCSK9) is increased in pro-inflammatory states and that elevated PCSK9 levels are associated with adverse cardiovascular outcomes after controlling for traditional risk factors, including low-density lipoprotein (LDL) cholesterol. Here we investigate PCSK9 as a novel link between inflammation and vascular EC dysfunction, as assessed by nitric oxide (NO) bioavailability. Tumor necrosis factor alpha (TNF-α), a pro-inflammatory cytokine, increased PCSK9 mRNA expression (1.98 [0.7, 3.4]-fold increase, p=0.02 vs. control) and PCSK9 protein levels (1.52±0.1-fold increase, p<0.01 vs. control) in isolated human aortic ECs. This was accompanied by reduced phosphorylated endothelial nitric oxide synthase (eNOS) protein which was 56% ± 5.6% of that in the controls (p<0.01) and NO bioavailability, which was reduced by 29% ± 22.1% compared to that in the controls (p<0.01). Finally, genetic PCSK9 reduction utilizing a PCSK9 specific siRNA in human aortic ECs resulted in the rescue of eNOS phosphorylation and NO bioavailability. Our results demonstrate that PCSK9 is increased in human aortic ECs exposed to a pro-inflammatory stimulus and that this increase is associated with EC dysfunction. Silencing of TNFα-mediated augmentation of PCSK9 protein expression utilizing a small interfering RNA against PCSK9 rescued the inflammation-induced EC dysfunction. These results indicate that PCSK9 is a causal link between inflammation and EC dysfunction, a potent driver of atherosclerotic cardiovascular disease. FUNDunding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Career Development Award from the American Heart Association, OAIC pilot Award

scholarly journals Proprotein Convertase Subtilisin/kexin Type 9 Links Inflammation to Vascular Endothelial Cell Dysfunction

2021 ◽  
Author(s):  
Thorsten M. Leucker ◽  
Nuria Amat-Codina ◽  
Stephen Chelko ◽  
Gary Gerstenblith
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cell ◽  
Vascular Endothelial Cell ◽  
Clinical Manifestations ◽  
Atherosclerotic Cardiovascular Disease ◽  
Vascular Endothelial ◽  
Proprotein Convertase ◽  
Protein Levels ◽  
No Bioavailability ◽  
Enos Protein

AbstractVascular endothelial cell (EC) dysfunction is a pathological mediator of he development, progression, and clinical manifestations of atherosclerotic disease. Inflammation is associated with EC dysfunction, but the responsible mechanisms are not well characterized. There is substantial evidence that serum proprotein convertase subtilisin/kexin type 9 (PCSK9) is increased in pro-inflammatory states and that elevated PCSK9 levels are associated with adverse cardiovascular outcomes after controlling for traditional risk factors, including low-density lipoprotein (LDL) cholesterol.Here we investigate PCSK9 as a novel link between inflammation and vascular EC dysfunction, as assessed by nitric oxide (NO) bioavailability. Tumor necrosis factor alpha (TNF-α), a pro-inflammatory cytokine, increased PCSK9 mRNA expression and PCSK9 protein levels in isolated human aortic ECs, which were accompanied by reduced total and phosphorylated endothelial nitric oxide synthase (eNOS) protein levels and NO bioavailability. Finally, genetic PCSK9 reduction utilizing a PCSK9 specific siRNA in human aortic ECs resulted in the rescue of phosphorylated eNOS protein levels and NO bioavailability.Our results demonstrate that PCSK9 is increased in human aortic ECs exposed to a pro-inflammatory stimulus and that this increase is associated with EC dysfunction. Silencing of TNFα-mediated augmentation of PCSK9 expression utilizing a small interfering RNA against PCSK9 rescued the inflammation-induced EC dysfunction. These results indicate that PCSK9 is a causal link between inflammation and EC dysfunction, a potent driver of atherosclerotic cardiovascular disease.

scholarly journals Immune Complex-Induced, Nitric Oxide-Mediated Vascular Endothelial Cell Death by Phagocytes Is Prevented with Decoy FcγReceptors

PLoS ONE ◽  
2016 ◽  
Vol 11 (4) ◽  
pp. e0153620 ◽  
Author(s):  
Ramanjaneya V. R. Mula ◽  
Deepa Machiah ◽  
Lauren Holland ◽  
Xinyu Wang ◽  
Harish Parihar ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cell Death ◽  
Endothelial Cell ◽  
Immune Complex ◽  
Vascular Endothelial Cell ◽  
Vascular Endothelial ◽  
Endothelial Cell Death

Procoagulant Albumin Increases Vascular Endothelial Cell Prostacyclin Secretion

1995 ◽  
Vol 74 (06) ◽  
pp. 1573-1577 ◽  
Author(s):  
David B Gubler ◽  
Chad R Ahlstrom ◽  
Lihua Liu ◽  
Jin-Feng Zhou ◽  
Charles J Parker ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cell ◽  
Platelet Function ◽  
Von Willebrand Factor ◽  
Vascular Endothelial Cell ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Cell Secretion ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryVascular endothelium regulates multiple aspects of platelet function through secretion of a variety of substances, including von Willebrand factor, nitric oxide, and prostacyclin (PGI2). The objective of this study was to determine whether procoagulant albumin (P-AI), a modified form of albumin present in normal human plasma could modulate endothelial cell secretion of these substances. P-AI did not affect constitutive secretion of von Willebrand factor or nitric oxide, but did increase PGI2 secretion in a time- and concentration-dependent manner. Pretreatment of endothelial cells with aspirin, or use of suramin, a broad- specificity inhibitor, prevented the response to P-AI. Prostaglandin H synthase-2 contributed to the P-AI-induced PGI2 secretion. These results indicate that in addition to inducing tissue factor activity and reducing protein C activation and fibrinolysis, P-AI also modulates vascular endothelial cell PGI2 secretion, and potentially, platelet function.

The role of caveolin-1 in PCB77-induced eNOS phosphorylation in human-derived endothelial cells

2007 ◽  
Vol 293 (6) ◽  
pp. H3340-H3347 ◽  
Author(s):  
Eun Jin Lim ◽  
Eric J. Smart ◽  
Michal Toborek ◽  
Bernhard Hennig
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Dna Binding ◽  
Vascular Endothelial Cell ◽  
Vascular Endothelial ◽  
Human Vascular Endothelial Cell ◽  
Caveolin 1 ◽  
Enos Phosphorylation

Polychlorinated biphenyls (PCBs) may contribute to the pathology of atherosclerosis by activating inflammatory responses in vascular endothelial cells. Endothelial nitric oxide synthase (eNOS) is colocalized with caveolae and is a critical regulator of vascular homeostasis. PCBs may be proatherogenic by causing dysfunctional eNOS signaling. The objective of this study was to investigate the role of caveolin-1 in PCB-induced endothelial dysfunction with a focus on mechanisms associated with eNOS signaling. Cells derived from an immortalized human vascular endothelial cell line were treated with PCB77 to study nitrotyrosine formation through eNOS signaling. Phosphorylation studies of eNOS, caveolin-1, and kinases, such as Src, phosphatidylinositol 3-kinase (PI3K), and Akt, were conducted in cells containing either functional or small-interfering RNA-silenced caveolin-1 protein. We also investigated caveolin-1-regulated mechanisms associated with PCB-induced markers of peroxynitrite formation and DNA binding of NF-κB. Cellular exposure to PCB77 increased eNOS phosphorylation and nitric oxide production, as well as peroxynitrite levels. A subsequent PCB-induced increase in NF-κB DNA binding may have implications in oxidative stress-mediated inflammatory mechanisms. The activation of eNOS by PCB77 treatment was blocked by inhibitors of the Src/PI3K/Akt pathway. PCB77 also increased phosphorylation of caveolin-1, indicating caveolae-dependent endocytosis. Caveolin-1 silencing abolished both the PCB-stimulated Akt and eNOS phosphorylation, suggesting a regulatory role of caveolae in PCB-induced eNOS signaling. These findings suggest that PCB77 induces eNOS phosphorylation in endothelial cells through a Src/PI3K/Akt-dependent mechanism, events regulated by functional caveolin-1. Our data provide evidence that caveolae may play a critical role in regulating vascular endothelial cell activation and toxicity induced by persistent environmental pollutants such as coplanar PCBs.

Cytotoxicity of IFN-γ and TNF-α for Vascular Endothelial Cell Is Mediated by Nitric Oxide

2002 ◽  
Vol 291 (4) ◽  
pp. 780-786 ◽  
Author(s):  
Junichi Yamaoka ◽  
Kenji Kabashima ◽  
Michiko Kawanishi ◽  
Ken-Ichi Toda ◽  
Yoshiki Miyachi
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cell ◽  
Vascular Endothelial Cell ◽  
Vascular Endothelial ◽  
Tnf Α ◽  
Ifn Γ
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