Inhibition of PCSK9 does not improve lipopolysaccharide-induced mortality in mice

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that targets LDL receptors (LDLRs) for degradation in liver. Blocking the interaction of PCSK9 with the LDLR potently reduces plasma LDL cholesterol levels and cardiovascular events. Recently, it has been suggested that inhibition of PCSK9 might also improve outcomes in mice and humans with sepsis, possibly by increasing LDLR-mediated clearance of endotoxins. Sepsis is a complication of a severe microbial infection that has shared pathways with lipid metabolism. Here, we tested whether anti-PCSK9 antibodies prevent death from lipopolysaccharide (LPS)-induced endotoxemia. Mice were administered PCSK9 antibodies prior to, or shortly after, injecting LPS. In both scenarios, the administration of PCSK9 antibodies did not alter endotoxemia-induced mortality. Afterward, we determined whether the complete absence of PCSK9 improved endotoxemia-induced mortality in mice with the germ-line deletion of Pcsk9. Similarly, PCSK9 knockout mice were not protected from LPS-induced death. To determine whether low LDLR expression increased LPS-induced mortality, Ldlr−/− mice and PCSK9 transgenic mice were studied after injection of LPS. Endotoxemia-induced mortality was not altered in either mouse model. In a human cohort, we observed no correlation between plasma inflammation markers with total cholesterol levels, LDL cholesterol, and PCSK9. Combined, our data demonstrate that PCSK9 inhibition provides no protection from LPS-induced mortality in mice.

Reduced plasma PCSK9 response in patients with bacteraemia is associated with mortality

“…Our results show that higher plasma PCSK9 levels are not detrimental in bacteraemia patients. It is also important to note that in an experimental model the inhibition of PCSK9 was not found to reduce LPS‐induced mortality in mice and that a slight rise in the incidence of upper respiratory tract infection was observed in patients treated with a PCSK9 inhibitor (2.1% alirocumab vs. 1.1% placebo) . Moreover, a recent study showed that a PCSK9 loss‐of‐function variant was not associated with an increased risk of hospitalization due to serious infection .…”

PCSK9 inhibition and inflammation: A narrative review

“…In the context of an optimal treatment strategy aimed at reducing CV risk, it is useful to identify effects that are specific or shared by either lipid lowering drugs, or anti-inflammatory drugs or a combination of both [139,144]. Moreover, since association studies do not necessarily imply a causal role of PCSK9 in the inflammatory response [145] and data from carriers of loss-of-function mutations in PCSK9, aimed to establish a correlation between plasma inflammation markers and PCSK9 levels are scanty and not conclusive [146,147], evidence Fig. 2.…”

Cardiovascular Events after Community-Acquired Pneumonia: A Global Perspective with Systematic Review and Meta-Analysis of Observational Studies

“…There are currently no published human studies exploring a potential effect of this new class of molecules on infection related outcomes. In an animal model, Berger et al did not show a reduction of lipopolysaccharide induced mortality with the administration of anti-PCSK9 antibodies [79].…”