PCSK9 and infection: A potentially useful or dangerous association?

Abstract

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.

Lipid-lowering therapy and renin-angiotensin-aldosterone system inhibitors in the era of the COVID-19 pandemic

“…In this context, there are no premises that PCSK9 inhibitors, because they are monoclonal antibodies (in relation to the above-mentioned high cytokine storm during infection), should be discontinued. In contrast, PCSK9 inhibitors should be continued to achieve further low-density lipoprotein cholesterol (LDL-C) lowering (based on "the lower, the better" principle), because then we might significantly stabilise atheroma plaque, reduce the risk of CVD events, and reduce inflammation [46][47][48]. Recent available data have confirmed the role of PCSK9 inhibition in reducing the process of inflammation via decreasing main vascular inflammatory markers, reducing infiltration of monocytes into the subendothelial layer, and inhibiting monocyte migration.…”

“…Apart from the reduction of pro-inflammatory mediators, PCSK9 inhibitors could ameliorate vascular inflammation [47]. Finally, a direct local anti-inflammatory action of PCSK9 inhibitors, independent of LDL-C reduction, has been shown in animal models; however, it still merits further investigation [47,48].…”

“…It is of special interest now (due to the fact that coronavirus might also use different receptors to enter the host cell) that treatment with PCSK9 inhibitors has beneficial effects on LDL-C lowering via inhibition of LDL-receptors (LDL-R). This might exert an antiviral effect, among others, on hepatitis C viral (HCV) infection through down-regulation of the surface expression of LDL-R and cluster of differentiation (CD) 81 on hepatic cells, and a positive association with increased inflammatory responses, as well as with septic shock [48]. In a recent paper, we confirmed that there is no association between PCSK9 levels and resistance to antibiotics or the condition of patients hospitalised in intensive care units, a finding of clinical importance in the COVID-19 infection era [49].…”

Familial hypercholesterolaemia and COVID‐19: triggering of increased sustained cardiovascular risk

“…Because PCSK9 inhibitors effectively lower LDL cholesterol and prevent acute coronary events in FH, their use should also be continued. PCSK9 inhibitors have a good safety profile; however, experience of their use in severely ill COVID-19 patients is limited and worthy of evaluation [8].…”

Association of a 3′ untranslated region polymorphism in proprotein convertase subtilisin/kexin type 9 with HIV viral load and CD4+ levels in HIV/hepatitis C virus coinfected women

“…CD81 and VLDLR are used by HCV to gain entry into cells [40] and PCSK9 levels modulate HCV infectivity in vitro [39] . The role of PCSK9 in inflammation, immunologic processes and infection is an area of active investigation [41, 42] .…”