Association between PCSK9 Levels and Markers of Inflammation, Oxidative Stress, and Endothelial Dysfunction in a Population of Nondialysis Chronic Kidney Disease Patients

Dounousi, Evangelia; Tellis, Constantinos C.; Pavlakou, Paraskevi; Duni, Αnila; Liakopoulos, Vassilios; Mark, Patrick B.; Papagianni, Αikaterini; Tselepis, Alexandros D.

doi:10.1155/2021/6677012

Cited by 15 publications

(12 citation statements)

References 58 publications

(60 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although mainly located in the liver PCSK9 is also expressed in vascular smooth muscle and endothelial cells and its expression is increased by stimulation with LPS (55), suggesting a critical role of PCSK9 in vascular function. Plasma PCSK9 levels have been shown to serve as a late biomarker of the severity of illness in patients with severe trauma injury in ICU (56) and sepsis (57) and have been correlated to endothelial dysfunction in patients with chronic kidney disease (58).…”

Section: Discussionmentioning

confidence: 99%

Colivelin, a synthetic derivative of humanin, ameliorates endothelial injury and glycocalyx shedding after sepsis in mice

et al. 2022

View full text Add to dashboard Cite

Endothelial dysfunction plays a central role in the pathogenesis of sepsis-mediated multiple organ failure. Several clinical and experimental studies have suggested that the glycocalyx is an early target of endothelial injury during an infection. Colivelin, a synthetic derivative of the mitochondrial peptide humanin, has displayed cytoprotective effects in oxidative conditions. In the current study, we aimed to determine the potential therapeutic effects of colivelin in endothelial dysfunction and outcomes of sepsis in vivo. Male C57BL/6 mice were subjected to a clinically relevant model of polymicrobial sepsis by cecal ligation and puncture (CLP) and were treated with vehicle or colivelin (100-200 µg/kg) intraperitoneally at 1 h after CLP. We observed that vehicle-treated mice had early elevation of plasma levels of the adhesion molecules ICAM-1 and P-selectin, the angiogenetic factor endoglin and the glycocalyx syndecan-1 at 6 h after CLP when compared to control mice, while levels of angiopoietin-2, a mediator of microvascular disintegration, and the proprotein convertase subtilisin/kexin type 9, an enzyme implicated in clearance of endotoxins, raised at 18 h after CLP. The early elevation of these endothelial and glycocalyx damage biomarkers coincided with lung histological injury and neutrophil inflammation in lung, liver, and kidneys. At transmission electron microscopy analysis, thoracic aortas of septic mice showed increased glycocalyx breakdown and shedding, and damaged mitochondria in endothelial and smooth muscle cells. Treatment with colivelin ameliorated lung architecture, reduced organ neutrophil infiltration, and attenuated plasma levels of syndecan-1, tumor necrosis factor-α, macrophage inflammatory protein-1α and interleukin-10. These therapeutic effects of colivelin were associated with amelioration of glycocalyx density and mitochondrial structure in the aorta. At molecular analysis, colivelin treatment was associated with inhibition of the signal transducer and activator of transcription 3 and activation of the AMP-activated protein kinase in the aorta and lung. In long-term outcomes studies up to 7 days, co-treatment of colivelin with antimicrobial agents significantly reduced the disease severity score when compared to treatment with antibiotics alone. In conclusion, our data support that damage of the glycocalyx is an early pathogenetic event during sepsis and that colivelin may have therapeutic potential for the treatment of sepsis-associated endothelial dysfunction.

show abstract

Section: Discussionmentioning

confidence: 99%

Colivelin, a synthetic derivative of humanin, ameliorates endothelial injury and glycocalyx shedding after sepsis in mice

et al. 2022

View full text Add to dashboard Cite

show abstract

“…However, being the effect of RYR mainly due to the presence of lovastatin, it is likely that an overexpression of PCSK9 may attenuate the reduction of LDL-C seen in animals treated with RYR. On the other hand, elevation of PCSK9 occurs under conditions of increased oxidative stress and inflammation [ 45 ]. This also explains the better response found with BPF compared to RYR.…”

Section: Discussionmentioning

confidence: 99%

Comparative Effect of Bergamot Polyphenolic Fraction and Red Yeast Rice Extract in Rats Fed a Hyperlipidemic Diet: Role of Antioxidant Properties and PCSK9 Expression

et al. 2022

View full text Add to dashboard Cite

Elevated serum cholesterol levels, either associated or not with increased triglycerides, represent a risk of developing vascular injury, mostly leading to atherothrombosis-related diseases including myocardial infarction and stroke. Natural products have been investigated in the last few decades as they are seen to offer an alternative solution to counteract cardiometabolic risk, due to the occurrence of side effects with the use of statins, the leading drugs for treating hyperlipidemias. Red yeast rice (RYR), a monacolin K-rich natural extract, has been found to be effective in counteracting high cholesterol, being its use accompanied by consistent warnings by regulatory authorities based on the potential detrimental responses accompanying its statin-like chemical charcateristics. Here we compared the effects of RYR with those produced by bergamot polyphenolic fraction (BPF), a well-known natural extract proven to be effective in lowering both serum cholesterol and triglycerides in animals fed a hyperlipidemic diet. In particular, BPF at doses of 10 mg/Kg given orally for 30 consecutive days, counteracted the elevation of both serum LDL cholesterol (LDL-C) and triglycerides induced by the hyperlipidemic diet, an effect which was accompanied by significant reductions of malondialdehyde (MDA) and glutathione peroxidase serum levels, two biomarkers of oxidative stress. Furthermore, the activity of BPF was associated to increased HDL cholesterol (HDL-C) levels and to strong reduction of Proprotein convertase subtilisin/kexin type 9 (PCSK9) levels which were found increased in hyperlipidemic rats. In contrast, RYR at doses of 1 and 3 mg/Kg, produced only significant reduction of LDL-C with very poor effects on triglycerides, HDL-C, glutathione peroxidase, MDA and PCSK9 expression. This indicates that while BPF and RYR both produce serum cholesterol-lowering benefits, BPF produces additional effects on triglycerides and HDL cholesterol compared to RYR at the doses used throughout the study. These additional effects of BPF appear to be related to the reduction of PCSK9 expression and to the antioxidant properties of this extract compared to RYR, thereby suggesting a more complete protection from cardiometabolic risk.

show abstract

“…Metformin and protamine demonstrate a similar effect, and they are already approved to use in humans to treat diabetes [198,199]. Some suggest utilization of PCSK9, considering their significant pleiotropic effect, but this is just a theory [200]. The potential effect of interfering with that pathway is a suppression of highly atherogenic Lp(a) [200].…”

Section: Therapeutic Implication Of the Post-sepsis Alterations In Lipid Profilementioning

confidence: 99%

“…Some suggest utilization of PCSK9, considering their significant pleiotropic effect, but this is just a theory [200]. The potential effect of interfering with that pathway is a suppression of highly atherogenic Lp(a) [200].…”

Section: Therapeutic Implication Of the Post-sepsis Alterations In Lipid Profilementioning

confidence: 99%

Persistence of Lipoproteins and Cholesterol Alterations after Sepsis: Implication for Atherosclerosis Progression

Laudański

2021

IJMS

View full text Add to dashboard Cite

(1) Background: Sepsis is one of the most common critical care illnesses with increasing survivorship. The quality of life in sepsis survivors is adversely affected by several co-morbidities, including increased incidence of dementia, stroke, cardiac disease and at least temporary deterioration in cognitive dysfunction. One of the potential explanations for their progression is the persistence of lipid profile abnormalities induced during acute sepsis into recovery, resulting in acceleration of atherosclerosis. (2) Methods: This is a targeted review of the abnormalities in the long-term lipid profile abnormalities after sepsis; (3) Results: There is a well-established body of evidence demonstrating acute alteration in lipid profile (HDL-c ↓↓, LDL-C -c ↓↓). In contrast, a limited number of studies demonstrated depression of HDL-c levels with a concomitant increase in LDL-C -c in the wake of sepsis. VLDL-C -c and Lp(a) remained unaltered in few studies as well. Apolipoprotein A1 was altered in survivors suggesting abnormalities in lipoprotein metabolism concomitant to overall lipoprotein abnormalities. However, most of the studies were limited to a four-month follow-up and patient groups were relatively small. Only one study looked at the atherosclerosis progression in sepsis survivors using clinical correlates, demonstrating an acceleration of plaque formation in the aorta, and a large metanalysis suggested an increase in the risk of stroke or acute coronary event between 3% to 9% in sepsis survivors. (4) Conclusions: The limited evidence suggests an emergence and persistence of the proatherogenic lipid profile in sepsis survivors that potentially contributes, along with other factors, to the clinical sequel of atherosclerosis.

show abstract

Association between PCSK9 Levels and Markers of Inflammation, Oxidative Stress, and Endothelial Dysfunction in a Population of Nondialysis Chronic Kidney Disease Patients

Cited by 15 publications

References 58 publications

Colivelin, a synthetic derivative of humanin, ameliorates endothelial injury and glycocalyx shedding after sepsis in mice

Colivelin, a synthetic derivative of humanin, ameliorates endothelial injury and glycocalyx shedding after sepsis in mice

Comparative Effect of Bergamot Polyphenolic Fraction and Red Yeast Rice Extract in Rats Fed a Hyperlipidemic Diet: Role of Antioxidant Properties and PCSK9 Expression

Persistence of Lipoproteins and Cholesterol Alterations after Sepsis: Implication for Atherosclerosis Progression

Contact Info

Product

Resources

About