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Proprotein Convertase Subtilisin/Kexin Type 9 and Atherosclerosis

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the last discovered member of the family of proprotein convertases (PCs), mainly synthetized in hepatic cells. This serine protease plays a pivotal role in the reduction of the number of low-density lipoprotein receptors (LDLRs) on the surface of hepatocytes, which leads to an increase in the level of cholesterol in the blood. The main anti-atherosclerotic effect of PCSK9 inhibitors results from their lipid-lowering efficiency.

  • Proprotein convertase subtilisin/kexin type 9
  • Atherosclerosis
  • Inflammation

1. Introduction

Proprotein convertases (PCs) are a family of nine serine proteases, which also includes proprotein convertase subtilisin/kexin type 9 (PCSK9). Each of those proteases plays a key role in post-translational modifications of propeptides leading to the formation of mature particles e.g., growth factors, enzymes, hormones, and transcriptional factors. Taking into consideration an ability for the activation of many substrates, to date, there seem to be a lot of physiological and pathophysiological processes that PCs take part in [1][2][3].

2. PCSK9 and Atherosclerosis

One of the main causes for the development of atherosclerosis is the deposition of excess LDL-C within the subendothelial matrix of selected arteries. Then transformed in the processes of oxidation, lipolysis and proteolysis into more reactive form—oxidized low-density lipoprotein (ox-LDL), it plays a key role in the initiation of atherogenesis [4]. Studies from the last few years have confirmed that PCSK9 accelerates the development of atherosclerosis due to the mechanism associated with increasing plasma concentration of LDL-C, but also by direct influence on the cells which build the arterial walls and atherosclerotic plaques [5][6][7]. Analysis of the metabolic pathways and PCSK9 functions in the vascular walls allows to predict the potentially beneficial anti-atherosclerotic effects associated with the therapeutical use of PCSK9 inhibitors [8].
The main anti-atherosclerotic effect of PCSK9 inhibitors results from their lipid-lowering efficiency. Data from the OSLER study indicate a significant reduction of LDL-C in the group of patients using evolocumab [9]. Similar results were observed in patients included in the ODYSSEY LONG TERM study, whose plasma LDL-C levels, after using alirocumab, were reduced by up to 62% compared with the placebo group [10].
Previous experiments revealed that PCSK9 inhibitors have a positive effect on the stabilization and morphology of atherosclerotic plaques, making them less vulnerable [11][12]. They also improve the function of platelets by reducing their thrombogenic potential [13][14][15]. Studies in which intravascular ultrasound (IVUS) was used suggest that the concentration of PCSK9 affects the size of the necrotic core within the atherosclerotic plaque, regardless of the concentration of LDL-C [5]. More detailed research carried out in 2020 showed that the use of PCSK9 inhibitors in therapy does not affect the size of the entire atherosclerotic plaque, but significantly improves its stabilization by reducing the lipid core burden index [16].
Arterial stiffness is acknowledged as one of the early predictors of cardiovascular disease [17]. For its indirect noninvasive assessment, pulse wave velocity (PWV) is widely used [18]. Positive correlation between circulating PCSK9 levels and arterial stiffness suggests another way (beyond lipid mechanism) for PCSK9 to affect cardiovascular risk [19]. Studies confirm improvements in arterial stiffness during therapy with PCSK9 inhibitors in patients with familial hypercholesterolemia [20][21][22].

3. Inflammation

Inflammatory processes play an important role in the pathophysiology of atherosclerosis [23]. Their intensification is associated with the development of atherogenesis. PCSK9 is capable of inducing the expression of pro-inflammatory cytokines such as tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β) or interleukin-6 (IL-6). Moreover, it enhances the translocations of transcriptional factors for pro-inflammatory cytokine genes into the cell nucleus and reduces the formation of anti-inflammatory cytokines in macrophages [24][25]. Furthermore, it was shown that PCSK9 regulates the concentration of sirtuins—a family of proteins involved in histone deacetylation, playing a key role in metabolic driver inflammation [26][27].
One of the first meta-analyses carried out on the influence of PCSK9 inhibitors on the inflammatory process did not show any correlation between these drugs and the concentration of C-reactive protein (CRP), a basic marker of the ongoing inflammatory process assessed in clinical practice [28]. Nevertheless, in the assessment of any single biomarker (such as CRP), a certain percentage of subjects with false positive and false negative results should be taken into consideration. To avoid these biases and improve diagnostic sensitivity, biomarker panels and index scores have been introduced in research for several years [29]. On the other hand, some studies reveal the beneficial effects of inhibition of PCSK9 using siRNA on lowering the concentrations of pro-inflammatory cytokines such as interleukin-1β (IL-1β), IL-6 and TNF-α [25][30].
Neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-HDL-cholesterol ratio (MHR) are the novel, widely available markers of inflammation in cardiovascular diseases [31]. High NLR or MHR ratio increases cardiovascular risk [22][32]. Studies show that PCSK9 inhibitors may improve the inflammatory status of patients with familial hypercholesterolemia (FH) described with the use of the above-mentioned parameters [22][32].

4. Monocytes, Macrophages and Foam Cells

The cells responsible for the secretion of PCSK9 in the vessels are smooth muscle cells (SMCs) and the endothelial cells [33]. Fully functional protein is also detected in atherosclerotic macrophages [34].
The process initiating the development of atherosclerotic plaques is the transformation of monocytes and macrophages into foam cells due to the accumulation of ox-LDL inside them. The influx of lipoproteins through the cell membrane takes place with the participation of many proteins, such as scavenger receptors (SRs), CD36, CD68, lectin-like ox-LDL receptor-1 (LOX-1) [35]. Macrophages excrete the excess of toxic cholesterol into the extracellular space and HDL-C by using membrane transporters, e.g., Adenosine Triphosphate Binding Cassette A1 (ABCA1). PCSK9 shifts the balance of cholesterol transport towards the interior of macrophages by regulating the expression of appropriate membrane proteins, contributing to the formation of foam cells and intensification of atherogenesis [24][36][37].
Apolipoprotein E (apoE), produced in macrophages and smooth muscle cells, is an anti-atherosclerotic protein. It acts via apolipoprotein E receptor-2 (apoER2), which reduces intracellular lipoprotein accumulation and inhibits the formation of foam cells and promotes the anti-inflammatory phenotype of macrophages. [38]. PCSK9 reduces apoER2 expression, attenuating the protective effect of apoE [39].
A very important mechanism of action of PCSK9 inhibitors, which reduces the diapedesis of monocytes into atherosclerotic plaques, is associated with the elevation of the concentration of anti-inflammatory interleukin-10 (IL-10). The increase in its concentration leads to the drop of the expression of TNF-α and C-C chemokine receptor type 2 (CCR2), which are responsible for the influx of monocytes into the atherosclerotic plaque [40][41][42].

5. Endothelial Cells

Endothelial cell apoptosis promoted by ox-LDL increases its dysfunction and creates favorable conditions for the development of atherosclerosis [35]. Experiments on human endothelial cells obtained from umbilical cord blood indicate that PCSK9 is involved in the enhancement of apoptosis caused by ox-LDL via the Bcl/Bax–caspase-9–caspase-3 pathway [43].
In response to the disturbed balance between the accumulation and removal of excess ox-LDL from the foam cells of the subendothelial matrix, the endothelial cells that are lining them receive a signal to produce pro-inflammatory and adhesive cytokines. One of the signal components is the presence of PCSK9 [44].
Reactive oxygen species (ROS) produced in excess in mitochondria, e.g., in the course of inflammation, a cornerstone in the pathogenesis of atherosclerosis [23], are capable of inducing endothelial cells damage, as well as activating inflammatory cells and thus intensifying the inflammatory process within the arterial wall [35]. Cells with silenced PCSK9 genes produce fewer ROS in their mitochondria [33], which may lead to the conclusion that inhibition of PCSK9 might reduce the risk of endothelial damage. To date, there are no clinical trials that would confirm such an effect of PCSK9 inhibitors.

6. Smooth Muscle Cells (SMCs)

Under the influence of PCSK9, smooth muscle cells acquire the ability to proliferate, migrate, synthesize collagen and uptake lipoproteins [35]. This cumulatively accelerates the formation of atherosclerotic plaques [45]. Moreover, under the influence of PCSK9, within SMCs, there is an increase in the production of vascular cell adhesion molecule 1 (VCAM-1), facilitating the process of macrophage infiltration into the atherosclerotic plaque [46]. So far, no studies have been carried out to assess the effect of PCSK9 inhibition on the concentration of adhesive factors in SMCs.

7. Coagulation and Platelet Aggregation

After several clinical trials, such as JUPITER, showed that the use of lipid-lowering therapy with statins reduces the cardiovascular risk much more strongly than it would result just from the decrease in plasma lipids, scientists began to consider other beneficial mechanisms responsible for this phenomenon [47]. Similar observations regarding cardiovascular risk were also made in the case of PCSK9 inhibitors [48].
One of the possible explanations indicates that cardiovascular risk might be related to thrombotic processes caused by inflammation in the vascular endothelium. CD46 and LOX-1 are involved in them [49][50] and, accompanied by ox-LDL binding protein, play a key role in the formation of blood clots [51]. A separate mechanism is associated with the toll-like receptor 2 (TLR-2) stimulation, which activates the process of platelet aggregation through lipid-peroxide-modified phospholipids in the transport of Lp(a) [52][53][54].
Due to the mechanisms described above, the use of PCSK9 inhibitors may limit the process of platelet aggregation in several ways, thus reducing the cardiovascular risk. The first one is by lowering the cholesterol level in the cell membrane of platelets, which results in the drop of their activity [55]. The second one is by decline in the LOX-1 and ox-LDL concentration [33][56]. The ultimate is by reduction of Lp(a) plasma level which decreases the activity of platelets via peroxide-modified phospholipids [57]. The above-mentioned ways of weakening the activity of platelets by inhibiting PCSK9 were unequivocally confirmed in a clinical trial from 2017, with the use of alirocumab and evolocumab, and associated with the reduction of cardiovascular risk [55].
Noteworthy is the influence of PCSK9 inhibitors on the incidence of venous thromboembolism, which is related to the inflammatory process in the endothelium and the atherogenesis [58][59]. The studies conducted so far have not shown a correlation between the concentration of LDL-C and the occurrence of venous thromboembolism [60], however, such a correlation was observed when Lp(a) levels were taken into account [61]. It is crucial in case of PCSK9 inhibitors, which in contrast to statins reduce both, to consider the plasma concentration of LDL-C, and Lp(a) [62]. For this reason, clinical trials have been conducted to assess the impact of alirocumab on the incidence of venous thromboembolism. The results clearly confirmed the beneficial effect of alirocumab therapy on the reduction of the risk of venous thromboembolism incidents, which was associated with a significant reduction in Lp(a) concentration [10]. The second plausible antithrombotic mechanism of PCSK9 inhibitor action, which requires further experimental studies, is associated with their ability to increase the clearance of blood-clotting factor VIII (FVIII)—the essential protein in coagulation processes [63].

This entry is adapted from 10.3390/metabo12030256

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