Differential Expression of PCSK9 Modulates Infection, Inflammation, and Coagulation in a Murine Model of Sepsis

Dwivedi, Dhruva J.; Grin, Peter M.; Khan, Momina; Prat, Annik; Zhou, Ji; Fox‐Robichaud, Alison; Seidah, Nabil G.; Liaw, Patricia C.

doi:10.1097/shk.0000000000000682

Cited by 115 publications

(115 citation statements)

References 39 publications

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“…The results of a recent in vivo study conducted by Dwivedi et al () who investigated the effects of differential PCSK9 expression on sepsis and inflammation were consistent with these findings. The results of this study suggest that, during induced sepsis, PCSK9 overexpression promotes bacterial dissemination, multiple organ failure, and tissue inflammation while reduced expression of PCSK9 suppresses systemic bacterial dissemination, organ damage, and inflammatory response.…”

Section: Role Of Pcsk9 In Sepsis and Septic Shocksupporting

confidence: 77%

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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Section: Role Of Pcsk9 In Sepsis and Septic Shocksupporting

confidence: 77%

PCSK9 and infection: A potentially useful or dangerous association?

Khademi

Momtazi‐Borojeni

Reiner

et al. 2017

Journal Cellular Physiology

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“…Dyspnoea, cyanosis, and overall grimace scores were increased in septic mice overexpressing PCSK9 relative to WT controls. Notably, bacterial load was significantly reduced in PCSK9 KO mice, showing also protection against systemic bacterial dissemination (Dwivedi et al, ). Similarly, it has been reported that humans carrying loss‐of‐function variants of the PCSK9 gene have increased survival during sepsis (Walley, ).…”

Section: Pcsk9 and Infectionsmentioning

confidence: 99%

PCSK9 at the crossroad of cholesterol metabolism and immune function during infections

Paciullo

Fallarino

Bianconi

et al. 2017

Journal Cellular Physiology

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Sepsis, a complex and dynamic syndrome resulting from microbial invasion and immune system dysregulation, is associated with an increased mortality, reaching up to 35% worldwide. Cholesterol metabolism is often disturbed during sepsis, with low plasma cholesterol levels being associated with poor prognosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes degradation of the low-density lipoprotein receptor (LDLR), thus regulating intracellular and plasma cholesterol levels. PCSK9 is often upregulated during sepsis and might have a detrimental effect on immune host response and survival. Accordingly, PCSK9 reduces lipopolysaccharide uptake and clearance by human hepatocytes. Moreover, PCSK9 upregulation exacerbates organ dysfunction and tissue inflammation during sepsis, whereas a protective effect of PCSK9 deficiency has been documented in septic patients. Although a possible detrimental impact of PCSK9 on survival has been described, some beneficial effects of PCSK9 on immune response may be hypothesized. First, PCSK9 is associated with increased plasma cholesterol levels, which might be protective during sepsis. Second, PCSK9, by stimulating LDLR degradation and inhibiting reverse cholesterol transport (RCT), might promote preferential cholesterol accumulation in macrophages and other immune cells; these events might improve lipid raft composition and augment toll-like receptor function thus supporting inflammatory response. Hence, a more clear definition of the role of PCSK9 in septic states might provide additional insight in the understanding of the sepsis-associated immune dysregulation and enhance therapeutic outcomes.

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“…This benefit endures; PCSK9 LOF patients had significantly lower rates of readmission or death after sepsis [71]. In a clinically relevant murine model of sepsis, we showed that: (1) PCSK9 knockout mice and (2) mice treated 6 h after the induction of peritonitis with a PCSK9-blocking antibody had a higher survival rate and lower inflammatory responses [57]. The therapies discussed in this section are summarized in Table 1.…”

Section: Personalized Medicine For Sepsismentioning

confidence: 99%

“…Furthermore, in humans, PCSK9 loss of function genotype was associated with increased 28-day survival (compared with the wild-type genotype) in 2 cohorts of patients with septic shock [56]. In an animal model of sepsis, PCSK9 knockout mice subjected to cecal ligation and puncture had lower bacterial concentrations in the blood, lungs, and peritoneal fluid than wild-type controls; PCSK9-overexpressing mice had higher bacterial concentrations in the blood, lungs, and peritoneal fluid [57]. Thus, the inhibition of PCSK9 has several potentially beneficial effects in sepsis and septic shock: (1) it increases hepatic clearance of pathogen endotoxins by increasing LDLR expression, and (2) it decreases the bacterial load in the peritoneum and, remarkably, also at remote sites (blood and lung).…”

Section: Management Of Organism and Organism Toxicity In Septic Shockmentioning

confidence: 99%

The Understanding and Management of Organism Toxicity in Septic Shock

Genga¹,

Shimada²,

Boyd

et al. 2018

J Innate Immun

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The toxicity caused by different organisms in septic shock is substantially complex and characterized by an intricate pathogenicity that involves several systems and pathways. Immune cells’ pattern recognition receptors initiate the host response to pathogens after the recognition of pathogen-associated molecular patterns. In essence, the subsequent activation of downstream pathways may progress to infection resolution or to a dysregulated host response that represents the hallmark of organ injury in septic shock. Likewise, the management of organism toxicity in septic shock is complicated and comprises a multiplicity of suitable targets. In this review, the classic immune responses to pathogens are discussed as well as other factors that are relevant in the pathogenicity of septic shock, including sepsis-induced immune suppression, inflammasome activation, intestinal permeability, and the role of lipids and proprotein convertase subtilisin/kexin type 9. Current therapies aiming to eliminate the organisms causing septic shock, recent and ongoing trials in septic shock treatment, and potential new therapeutic strategies are also explored.

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Differential Expression of PCSK9 Modulates Infection, Inflammation, and Coagulation in a Murine Model of Sepsis

Cited by 115 publications

References 39 publications

PCSK9 and infection: A potentially useful or dangerous association?

PCSK9 and infection: A potentially useful or dangerous association?

PCSK9 at the crossroad of cholesterol metabolism and immune function during infections

The Understanding and Management of Organism Toxicity in Septic Shock

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