Abstract:Sepsis is a life-threatening organ dysfunction syndrome caused by a dysregulated host response to infection. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is often upregulated in the presence of sepsis and infectious diseases. In sepsis, PCSK9 degraded the low-density lipoprotein cholesterol (LDL) receptors (LDL-R) of the hepatocytes and the very low-density lipoprotein cholesterol receptors (VLDL-R) of the adipocytes, which then subsequently reduced pathogenic lipid uptake and clearance/sequestration.… Show more
“…Clinical studies have proved that the level of PCSK9 in serum of patients with sepsis increased, and PCSK9 is regarded as a biomarker of sepsis [27]. Another studies have shown that the expression level of PCSK9 is positively correlated with the pathological damage of liver and kidney in septic mice [12,28]. In the current study, we found for the rst time that PCSK9 increased in LPS-treated HUVECs and the aortas of CLP-induced septic mice.…”
Section: Discussionsupporting
confidence: 54%
“…PCSK9 is associated with the formation of atherosclerotic plaques and inhibition of it has been showed to be bene cial to vascular function [10]. In addition, the negative role of PCSK9 in sepsis has also been gradually revealed by some studies [11,12].…”
Endothelial dysfunction often accompanies sepsis. We aimed to explore the role of PCSK9 in septic endothelial dysfunction. Sepsis was induced by Lipopolysaccharide (LPS) treatment on human umbilical vein endothelial cells (HUVECs) in vitro and Cecal ligation and puncture (CLP) surgery mice in vivo. Evolocumab (EVC) and Pep 2-8, PCSK9 inhibitors, was subsequently used to determine the role of PCSK9 in septic endothelial dysfunction in vitro and in vivo, respectively. And TLR4 agonist, Kdo2-Lipid A ammonium (KLA), was used to determine the related mechanism. Expression of eNOS, VE-Cadherin, PCSK9, TLR4, MYD88, p-p65, p65, NLRP3, ASC and Caspase1 p20 in the aortas and HUVECs were measured by Western blot and mRNA expression of TNFα, IL-1 and IL-6 were determined by PCR. Nitric oxide (NO) content in the medium and cell viability were examined. Vasodilation function of the aorta was detected by vascular reactivity experiments. The 48-h survival rate after CLP was observed. The results demonstrated that the expression of eNOS and VE-Cadherin decreased and PCSK9 expression increased in septic HUVECs or mice. Nevertheless, inhibition of PCSK9 could improve the eNOS and VE-Cadherin expression. The activation of TLR4/MyD88/NF-κB and NLRP3 pathways should be responsible for the PCSK9-induced endothelial dysfunction in sepsis. Vascular reactivity test and survival study shows that inhibiting PCSK9 could prevent the decline of endothelium-dependent vasodilation function and improve the survival rates of septic mice. In summary, our results suggest that increased PCSK9 in sepsis activates the TLR4/MyD88/NF-κB and NLRP3 pathways to induce inflammation, which results in vascular endothelial dysfunction and decrease of survival rates. However, inhibition of PCSK9 could improve the vascular endothelial function in sepsis, which may be a potential way for clinical treatment.
“…Clinical studies have proved that the level of PCSK9 in serum of patients with sepsis increased, and PCSK9 is regarded as a biomarker of sepsis [27]. Another studies have shown that the expression level of PCSK9 is positively correlated with the pathological damage of liver and kidney in septic mice [12,28]. In the current study, we found for the rst time that PCSK9 increased in LPS-treated HUVECs and the aortas of CLP-induced septic mice.…”
Section: Discussionsupporting
confidence: 54%
“…PCSK9 is associated with the formation of atherosclerotic plaques and inhibition of it has been showed to be bene cial to vascular function [10]. In addition, the negative role of PCSK9 in sepsis has also been gradually revealed by some studies [11,12].…”
Endothelial dysfunction often accompanies sepsis. We aimed to explore the role of PCSK9 in septic endothelial dysfunction. Sepsis was induced by Lipopolysaccharide (LPS) treatment on human umbilical vein endothelial cells (HUVECs) in vitro and Cecal ligation and puncture (CLP) surgery mice in vivo. Evolocumab (EVC) and Pep 2-8, PCSK9 inhibitors, was subsequently used to determine the role of PCSK9 in septic endothelial dysfunction in vitro and in vivo, respectively. And TLR4 agonist, Kdo2-Lipid A ammonium (KLA), was used to determine the related mechanism. Expression of eNOS, VE-Cadherin, PCSK9, TLR4, MYD88, p-p65, p65, NLRP3, ASC and Caspase1 p20 in the aortas and HUVECs were measured by Western blot and mRNA expression of TNFα, IL-1 and IL-6 were determined by PCR. Nitric oxide (NO) content in the medium and cell viability were examined. Vasodilation function of the aorta was detected by vascular reactivity experiments. The 48-h survival rate after CLP was observed. The results demonstrated that the expression of eNOS and VE-Cadherin decreased and PCSK9 expression increased in septic HUVECs or mice. Nevertheless, inhibition of PCSK9 could improve the eNOS and VE-Cadherin expression. The activation of TLR4/MyD88/NF-κB and NLRP3 pathways should be responsible for the PCSK9-induced endothelial dysfunction in sepsis. Vascular reactivity test and survival study shows that inhibiting PCSK9 could prevent the decline of endothelium-dependent vasodilation function and improve the survival rates of septic mice. In summary, our results suggest that increased PCSK9 in sepsis activates the TLR4/MyD88/NF-κB and NLRP3 pathways to induce inflammation, which results in vascular endothelial dysfunction and decrease of survival rates. However, inhibition of PCSK9 could improve the vascular endothelial function in sepsis, which may be a potential way for clinical treatment.
“…The LDLR clears, in an LDL-dependent mechanism, gram-positive lipoteichoic acid and gram-negative LPS, known to exacerbate sepsis pathophysiology ( 223 ). Because the protective effect of the lack of PCSK9 is abrogated in LDLR KO mice, it was proposed that the lack of PCSK9, or the use of PCSK9 inhibitors ( 224 , 225 ), would enhance pathogen lipid clearance via the LDLR. Using a cecal ligation and puncture model of sepsis, PCSK9 KO mice were indeed reported to have lower bacterial concentrations in the blood, lungs, and peritoneal cavity fluid than WT animals, suggesting that loss of PCSK9 improves bacterial suppression/clearance ( 222 ).…”
This article reviews the discovery of PCSK9, its structure-function characteristics, and its presently known and proposed novel biological functions. The major critical function of PCSK9 deduced from human and mouse studies, as well as cellular and structural analyses, is its role in increasing the levels of circulating LDL-cholesterol (LDLc), via its ability to enhance the sorting and escort of the cell surface LDL receptor (LDLR) to lysosomes. This implicates the binding of the catalytic domain of PCSK9 to the EGF-A domain of the LDLR. This also requires the presence of the C-terminal Cys/His-rich domain (CHRD), its binding to the secreted cytosolic cyclase associated protein 1 (CAP-1), and possibly another membrane-bound “protein X”. Curiously, in PCSK9-deficient mice, an alternative to the downregulation of the surface levels of the LDLR by PCSK9 is taking place in the liver of female mice in a 17β-estradiol-dependent manner by still an unknown mechanism. Recent studies have extended our understanding of the biological functions of PCSK9, namely its implication in septic shock, vascular inflammation, viral infections (Dengue; SARS-CoV-2) or immune checkpoint modulation in cancer via the regulation of the cell surface levels of the T-cell receptor and MHC-I, which govern the anti-tumoral activity of CD8 + T cells. Because PCSK9 inhibition may be advantageous in these processes, the availability of injectable safe PCSK9 inhibitors (PCSK9i) that reduces by 50-60% LDLc above the effect of statins is highly valuable. Indeed, injectable PCSK9 mAb or siRNA could be added to current immunotherapies in cancer/metastasis.
“…Finally, the future will tell what other functions of PCSK9 could be targeted in pathologies distinct from hypercholesterolemia, such as in cancer/metastasis, viral infections (Fig. 6) and possibly uncontrolled inflammatory or immune reactions, e.g., in sepsis (151) implicating pathogen lipid clearance via the LDLR (152)(153)(154)(155), in vascular inflammation (156), and in platelet activation (157). domain of the LDLR, as well as the hydrophobic interaction of Leu 108 of the prodomain of PCSK9 with Leu 626 in the -barrel domain of the LDLR (dashed red ellipse) (87).…”
Section: Discussionmentioning
confidence: 99%
“…Finally, the future will tell what other functions of PCSK9 could be targeted in pathologies distinct from hypercholesterolemia, such as in cancer/metastasis, viral infections ( Fig. 6 ), and possibly uncontrolled inflammatory or immune reactions, for example, in sepsis ( 151 ) implicating pathogen lipid clearance via the LDLR ( 152 , 153 , 154 , 155 ), in vascular inflammation ( 156 ), and in platelet activation ( 157 ). Fig.…”
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