https://orcid.org/0000-0003-0384-2097
Abstract
PCSK9 degrades low-density lipoprotein cholesterol (LDL) receptors and subsequently increases serum LDL cholesterol. Clinical trials show that inhibition of PCSK9 efficiently lowers LDL cholesterol levels and reduces cardiovascular events. PCSK9 inhibitors also reduce the extent of atherosclerosis. Recent studies show that PCSK9 is secreted by vascular endothelial cells, smooth muscle cells, and macrophages. PCSK9 induces secretion of pro-inflammatory cytokines in macrophages, liver cells, and in a variety of tissues. PCSK9 regulates toll-like receptor 4 expression and NF-κB activation as well as development of apoptosis and autophagy. PCSK9 also interacts with oxidized-LDL receptor-1 (LOX-1) in a mutually facilitative fashion. These observations suggest that PCSK9 is inter-twined with inflammation with implications in atherosclerosis and its major consequence—myocardial ischaemia. This relationship provides a basis for the use of PCSK9 inhibitors in prevention of atherosclerosis and related clinical events.
1. Introduction
Proprotein convertase subtilisin/kexin type 9 (PCSK9) degrades low-density lipoprotein cholesterol receptors (LDLr) and subsequently raises low-density lipoprotein cholesterol (LDL-C) levels. Understanding of PCSK9 biology has fuelled much interest in PCSK9 inhibitors. Although the existence of this molecule was known for many years,1,2 data on prevention of cardiovascular events was unravelled only in the last few years.3 While the primary effect of PCSK9 inhibitors is mediated through up-regulation of LDLr and subsequent dramatic lowering of circulating LDL-C levels, mounting evidence suggests possible pleiotropic effects of PCSK9. One such effect seems to be modulation of inflammatory mechanisms in atherosclerotic cardiovascular disease (ASCVD).
Chronic inflammation has been widely recognized as a hallmark of ASCVD with evidence supporting a role of inflammation in the initiation, progression and rupture of an atherosclerotic plaque. Various inflammatory mediators and scavenger receptors (SRs) such as lectin-like oxidized lipoprotein-1 (LOX-1) have been implicated in inflammatory responses in atherosclerosis. More recently, role of PCSK9 in atherogenesis has gained considerable interest with direct as well as indirect pro-inflammatory effects mediated by interactions with LOX-1 and other SRs. This interplay provides a novel basis for the efficacy of PCSK9 inhibitors.
Here, we review the biology of PCSK9 and evidence for its pro-inflammatory effects which may have implications in the efficacy of PCSK9 inhibitors in ASCVD.
2. PCSK9 inhibition and LDL-C lowering—clinical evidence of benefit
PCSK9, the 9th member of the proprotein convertase family, is a group of serine protease enzymes. It was first described by Abifadel et al.2 who identified a gain-of-function mutation of this gene in a French family with familial hypercholesterolaemia. On the other hand, loss of function was shown to be associated with extremely low levels of LDL-C.3 LDL particles in the blood bind to LDLr on the hepatocyte surface. This LDL-LDLr complex is then internalized by endocytosis and merges with lysosomes. The LDL is subsequently digested in the lysosome, while LDLr is recycled back to the hepatocyte surface for further binding of LDL and endocytosis. PCSK9 induces degradation of LDLr, inhibits LDLr recycling and increases circulating LDL-C levels.4,5
This discovery led to the revolutionary proposition that inhibition of PCSK9-mediated LDLr degradation would drastically reduce LDL-C levels and decrease cardiovascular risk. PCSK9 inhibition through monoclonal antibodies like alirocumab and evolocumab emerged as a novel treatment of hypercholesterolaemia and related cardiovascular diseases. Given the consistent success in achieving massive reduction in LDL-C levels (by ≈50% as monotherapy and ≈70% in combination with statins) with good safety profile, the Food and Drug Administration approved alirocumab and evolocumab for the management of patients with either familial hyperlipidaemia or ASCVD who need additional LDL-C lowering.
In the OSLER trial (open-label study of long-term evaluation against LDL-C) that included 4465 patients, treatment with evolocumab reduced LDL-C by 61%. The incidence of cardiovascular events was also reduced in the evolocumab-treated group (1% vs. 2% in the standard therapy group, P = 0.0003).6 A post hoc analysis of 2341 patients enrolled in the ODYSSEY LONG TERM study (long-term safety and tolerability of alirocumab in high cardiovascular risk patients with hypercholesterolaemia not adequately controlled with lipid modifying therapy) showed a similar reduction (61%) in LDL-C levels and lower rates of cardiovascular events with use of alirocumab (1.7% vs. 3.3%, P = 0.02).7 However, cardiovascular events were relatively few in these studies to accurately address the outcomes issue. The FOURIER trial (further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk) enrolled 27 564 ASCVD patients on statin therapy and randomized to evolocumab or placebo. Evolocumab-treated group had a 59% reduction in LDL-C from a median level of 92 mg/dL to 30 mg/dL at 48 weeks, and a 1.5% absolute reduction in cardiovascular events, primarily driven by non-fatal myocardial infarction (MI), stroke, and revascularization. However, no benefit in overall or cardiovascular-specific mortality was seen despite massive LDL-C lowering.8 The FOURIER trial raised concerns that we may have reached the limit of cardiovascular benefits from LDL-C lowering. However, the recent ODYSSEY OUTCOMES trial in patients with recent acute coronary syndrome showed that the use of alirocumab was associated with a significant reduction in recurrent ischaemic cardiovascular events as well as in mortality form composite of death from any cause, non-fatal MI, or non-fatal ischaemic stroke.9
It is noteworthy that elevated LDL-C is only one of the many components in the development of atherosclerosis. Chronic inflammation, either as a result of dyslipidaemia or other factors such as hypertension, diabetes, and smoking, has been well-established as the final common pathway in the development and progression of atherosclerosis.
The combination of statin therapy and PCSK9 inhibition markedly lowers LDL-C and reduces cardiovascular events. Whether residual inflammatory risk as measured by on-treatment high-sensitivity C-reactive protein (hsCRP) remains unclear. Recently, Pradhan et al.10 evaluated residual inflammatory risk among 9738 patients participating in the SPIRE-1 and SPIRE-2 cardiovascular outcomes trials, who were receiving both statin therapy and bococizumab, according to on-treatment levels of hsCRP (hsCRPOT) and LDL-COT measured 14 weeks after drug initiation. Their data showed that elevated levels of hsCRPOT remain a significant predictor of future cardiovascular risk among patients with stable atherosclerosis treated with statins and PCSK9 inhibition concomitantly. This evidence of residual inflammatory risk despite maximal LDL-C lowering suggests that modulation of inflammation offers additional opportunity for cardiovascular risk reduction.
3. Inflammation in atherosclerosis and PCSK9
ASCVD is thought to be an inflammatory process.11 Recent studies using multiterritorial positron emission tomography–magnetic resonance imaging have characterized arterial inflammation in middle-aged individuals with subclinical atherosclerosis, suggesting the presence of inflammatory state in the early stages of atherosclerosis.12
Mechanistically, endothelial injury and activation results in the expression of surface molecules to which inflammatory cells attach. This is followed by migration of monocytes and macrophages across the endothelium and their sub-intimal accumulation. These cells during activation release cytokines and create a pro-inflammatory milieu. Over time, oxidized-LDL (ox-LDL) in circulation is taken up by SRs such as SR-A, CD36, and LOX-1 on the surface of endothelial cells (ECs) and enters the vascular media.13 Monocytes/macrophages and vascular smooth muscle cells (VSMCs) via LOX-1 imbibe ox-LDL and leads to the formation of foam cells.14 The expression of SRs is up-regulated in the pro-inflammatory milieu. For instance, LOX-1 expression has been shown to increase in response to lipopolysaccharide, angiotensin II and pro-inflammatory cytokines.15 Importantly, anti-inflammatory therapy directed at inflammatory cascade and ox-LDL receptors LOX-1 and CD36, particularly LOX-1, has shown promise in reducing atherosclerotic burden in experimental studies.15–17 On the other hand, LOX-1 overexpressing mice exhibit accelerated atherosclerotic lesion formation in association with an inflammatory state.17,18
Atherosclerotic plaques express PCSK9 as evident from immunohistochemistry and western blotting. Most of the PCSK9 expression is in the VSMCs.17 In keeping with the postulated role of PCSK9 in atherogenesis, overexpression of PCSK9 has been shown to increase atherosclerotic plaque size.19 This phenomenon is not observed in LDLr−/− mice, suggesting that the effects of PCSK9 on atherogenesis are LDLr-dependent.20 In keeping with the animal data, continues use of PCSK9 antibody was shown by Nicholls et al.21 to reduce coronary atherosclerosis modestly, but significantly.
A major consequence of atherosclerosis is myocardial ischaemia. Ischaemic myocardium reveals intense inflammation with release of pro-inflammatory cytokines into circulation.22,23 There is a significant increase in pro-inflammatory biomarkers, such as hsCRP, tumour necrosis factor α (TNFα), interleukin (IL)-6, IL-1β, sLOX-1, and others, in patients with myocardial ischaemia, especially in the acute phase.22,23 A recent clinical trial has shown a significant benefit of anti-inflammatory therapy with the IL-1β inhibitor Canakinumab in terms of reducing clinical events.24 Several other clinical trials assessing the efficacy of anti-inflammatory therapy are currently underway. Whether PCSK9 inhibition represents one such gateway of modulating the inflammatory response in atherosclerosis is under investigation.
4. Pro-inflammatory stimuli and PCSK9
Although liver is the predominant source of PCSK9, this enzyme is also expressed in extra-hepatic tissues, such as kidney, small intestine, brain, heart, and the blood vessels (Figure 1). Pro-inflammatory stimuli TNFα and LPS enhance the expression of PCSK9 in vascular ECs and VSMCs.25,26 Treatment of human hepatocytes with resistin, found in inflammatory zone 3 (FIZZ3), is also associated with intense PCSK9 expression.27
Pro-inflammatory factors regulate PCSK9 secretion in different organs. Pro-inflammatory factors, such as LPS, ox-LDL, TNF-α, and IL-1β, induce PCSK9 secretion not only in liver, kidney, and small intestine (main sources for PCSK9) but also in brain, heart, and artery. Through degradation of LDLr, PCSK9 is involved in hyperlipidaemia, atherosclerosis, diabetes, hypertension, myocardial ischaemia, and stroke.
Serum PCSK9 levels correlate with serum LDL-C levels and other coronary risk factors.28 High serum PCSK9 levels have been noted in patients with systemic inflammatory response syndrome and sepsis.29 Elevated PCSK9 levels are associated with new plaque formation after adjusting for LDL-C levels and other risk factors.30 The ATHEOROREMO-IVUS study showed a correlation of serum PCSK9 levels with coronary plaque inflammation and absolute volume of necrotic core tissue.31 Almontashiri et al.32 reported elevated serum PCSK9 levels in patients with acute MI in two independent retrospective angiographic studies. We have observed elevated serum PCSK9 levels in patients with myocardial ischaemia, particularly in those with recent onset (unpublished data). In these studies, there was a significant correlation between serum levels of PCSK9 and pro-inflammatory cytokines—IL-6, IL-1β, TNFα, and MCSF as well as hsCRP.
5. Oxidized LDL, inflammatory mediators, and PCSK9
Ox-LDL is a potent pro-inflammatory mediator of atherosclerosis.33 It and other pro-inflammatory mediators, such as LPS, have been shown to induce PCSK9 expression in macrophages, ECs, VSMCs, and dendritic cells, which are key players in the evolution of atherosclerosis.33 The intermediate steps leading to the expression and release of PCSK9 include activation of toll-like receptors (TLRs), NLRP3 inflammasome, and NF-κB.34 Release of IL-1β and IL-18 (IL-1β ≫ IL-18) in response to NLRP3 inflammasome also appears to play a critical role in the transcription of PCSK9. TLR4 activation via TRIF and MyD88 pathways (MyD88 ≫ TRIF) induces the transcription of PCSK9 in aorta (Figure 2).34 In keeping with these observations, PCSK9 is noted to be highly expressed in atherosclerotic regions, predominantly in the VSMCs.25
Inflammation and PCSK9. Inflammatory factors like ox-LDL and LPS activate toll-like receptors and NLRP3 inflammasome resulting in enhanced expression of PCSK9.
Apoptosis is a hall-mark of growing plaque as well as rupture-prone plaque.35 Recently, Ding et al. have suggested the existence of a positive feedback interplay between VSMC-derived PCSK9 and mitochondrial DNA damage resulting in apoptosis that is mediated through mtROS.26
Human recombinant PCSK9 has been shown to directly activate human macrophages as indicated by macrophage migration and release of pro-inflammatory cytokines. Liu et al.36 showed that PCSK9 plays a role in ox-LDL‐induced dendritic cell maturation and activation of T cells from human blood and atherosclerotic plaque. Using microarray analysis to study gene expression profile in liver cells treated with recombinant PCSK9, Lan et al.37 demonstrated that PCSK9 not only affected the response to stress and inflammation but also activated several other pathways such as cell cycle and xenobiotic metabolism. It is of note that loss of function mutation of the PCSK9 gene has been associated with an attenuated cytokine response in both healthy and septic patients after LPS administration. Serum IL-1β levels after treatment with LPS were found to be significantly lower in mice with PCSK9 gene deletion, compared to wild-type mice.38 In addition, recombinant PCSK9 administration enhances transcription of pro-inflammatory cytokines TNFα and IL-1β, and suppresses mRNA levels of anti-inflammatory cytokines in LPS-stimulated macrophages. As mentioned earlier, human studies also reveal a correlation between serum levels of PCSK9 and IL-1β and other pro-inflammatory cytokines in subjects with asymptomatic and symptomatic ASCVD, particularly in patients with acute myocardial ischaemia. These observations in the in vitro setting as well as in animal and human models of cardiovascular disease strongly support the concept that a pro-inflammatory milieu enhances PCSK9 expression and release. Of note, PCSK9 itself potentiates the inflammatory state.
Many recent studies have suggested a role for PCSK9 in the development of atherosclerosis beyond LDL-C lowering. Tavori et al.38 reported that PCSK9 in the arterial wall stimulates monocyte migration into the atheroma. PCSK9 activation has been noted to be responsible for increased LDL uptake in macrophages and reverse cholesterol transport.39 Ding et al.40 demonstrated that recombinant PCSK9 increased the expression of multiple SRs, such as LOX-1, SRA, and CD36, with LOX-1 being the most up-regulated SR. These SRs are major mediators of ox-LDL uptake by macrophages in the initiation of atherosclerosis. Adorni et al.41 showed that PCSK9 plays a pivotal role in cholesterol efflux from foam cells through regulation of adenosine triphosphate-binding cassette transporters ABCA1 and ABCG1.
Despite encouraging pre-clinical data, a recent post hoc analysis showed that the combination of high-intensity statin therapy and PCSK9 inhibition does not fully address the inflammatory mechanisms of atherothrombosis, with treated patients continuing to show persistently elevated levels of circulating hsCRP.10 Similar lack of correlation between baseline levels of hsCRP and efficacy of PCSK9 inhibitors in reducing adverse cardiovascular outcomes was also noted in the FOURIER trial.42 These observations suggest that either there was no change in inflammation as measured by hsCRP, or hsCRP is only one non-specific marker of inflammation and may not reflect the entire spectrum of inflammation. In unpublished studies, we have found a strong correlation between markers of inflammation and PCSK9 in plasma in patients with coronary atherosclerosis.
6. Shear stress and PCSK9
Haemodynamic shear stress is a major determinant of atherogenesis. It is the frictional force acting on ECs and VSMCs of the vascular channel, which leads to changes in vascular biology and release of biochemical signals. VSMCs are exposed to shear stress driven by pressure gradient along the length of vascular channels. During state of health when the EC lining is intact, exposure of SMCs to shear stress is limited, but when EC lining is disrupted as during angioplasty or surgical endarterectomy, alterations in shear stress may directly influence VSMC function.
Steady laminar shear stress (10–20 dyn/cm2) promotes EC survival, and inhibits coagulation, leucocyte diapedesis, and smooth muscle cell proliferation. Laminar shear stress is considered atheroprotective. Low shear stress (1–5 dyn/cm2) or disturbed shear stress induces EC dysfunction, characterized by poor cell alignment and high turnover.43 Low shear stress also up-regulates transcription factors AP-1 and NF-kB that promote a pro-oxidant and pro-inflammatory state. High shear stress (>25 dyn/cm2) with sustained laminar shear stress, on the other hand, increases expression of genes that are protective against atherosclerosis.
Low shear stress disturbs the integrity of EC layer resulting in exposure of the underlying VSMCs which then undergo proliferation and migration. Ding et al.26 investigated the role of shear stress on PCSK9 expression in ECs and VSMCs during an inflammatory state. They observed that PCSK9 expression was much higher in VSMCs than in ECs at all levels of shear stress. Importantly, there was greater expression of PCSK9 in aortic arch branch points and aorta–iliac bifurcation regions where the shear stress is low, and atherosclerosis develops preferentially, than in the thoracic aorta and iliac arteries, areas that are relatively protected from development of atherosclerosis. Further studies indicated that changes in reactive oxygen species (ROS) generation paralleled the changes in PCSK9 expression at all levels of shear stress.26 These observations suggest that altered state of PCSK9 expression may contribute to the development of atherosclerosis in regions of low and disturbed shear stress in a pro-inflammatory milieu. These concepts are summarized in Figure 3.
Shear stress regulates atherogenesis via PCSK9. Compared with physiological shear stress, high shear stress inhibits, while low or disturbed shear stress induce PCSK9 expression in vascular ECs and SMCs or macrophages. PCSK9 secreted by vascular cells further regulates the localization of atherosclerosis. Reactive oxygen species (ROS) and the transcription factor NF-kB play an important role in signalling.
7. Autophagy, apoptosis, and PCSK9
Autophagy is a natural, self-regulated mechanism by which a cell disassembles unnecessary or dysfunctional components. It is considered a protective mechanism that promotes cell survival. Some level of autophagy is observed at baseline in the vascular tissues and the heart, but it is strongly up-regulated in the ischaemic heart. Studies have demonstrated that autophagy is activated in VSMCs and cardiomyocytes in response to pro-inflammatory cytokines and angiotensin II.44 Blockade of these inflammatory mediators has been shown to limit autophagy as well as cardiac injury in experimental models. This suggests that activation of autophagy during ischaemia may be a compensatory response to combat cellular injury. Investigations in our laboratory have revealed that PCSK9 inhibition by siRNA transfection or gene deletion markedly reduces ischaemia-driven autophagy in primary mouse cardiomyocytes.44 Further studies revealed activation of ROS-ATM-LKB1-AMPK axis as a possible mechanism of PCSK-induced autophagy (Figure 4). Hearts of humans with recent infarcts also showed expression of PCSK9 and autophagy in the border zone-similar to that in the infarcted mouse heart.44
PCSK9, autophagy, and apoptosis. In a pro-inflammatory milieu, low concentration of PCSK9 induces autophagy, while high concentration of PCSK9 activates apoptosis. The balance of autophagy and apoptosis determines cell death, and plays key role in atherosclerosis and myocardial ischaemia. Panel on the left shows the signalling involved in the development of autophagy.
Apoptosis of VSMCs and macrophages is a hallmark of atherosclerosis. A link between cellular apoptosis and expression of PCSK9 in VSMCs was demonstrated in a recent study.45 Incubation of VSMCs with recombinant PCSK9 increased apoptosis, measured by expression of caspace-3, Bax and Bcl-2. As evidence for the direct pro-apoptotic effect of PCSK9, treatment of VSMCs with a synthetic PCSK9 inhibitor Pep2-8 attenuated this process, suggesting a causal relationship. These concepts are partly summarized in Figure 4.
8. Inflammation and PCSK9 in myocardial ischaemia
Inflammation plays a significant role in the determination of infarct size and cardiac function after coronary occlusion. The ischaemic regions, particularly the zone bordering the infarct area, show apoptosis as well as autophagy; these are complex processes that determine eventual infarct size and cardiac contractile function. In a recent study in mice subjected to coronary artery occlusion, we reported intense expression of PCSK9 in the zone bordering the infarcted areas soon after ischaemic insult.46 PCSK9 expression also determined infarct size and residual cardiac contractile function since mice lacking the PCSK9 gene or wild-type mice pre-treated with synthetic PCSK9 inhibitors had smaller infarct size and preserved cardiac function. Further, there was development of autophagy in the border zone with increased PCSK9 expression. In cultured cardiomyocytes, we demonstrated that hypoxia and the pro-inflammatory cytokine TNFα induced the expression of PCSK9. The relationship between PCSK9 expression and autophagy was also studied in primary mice cardiomyocytes. Hypoxia, inflammation, and ROS were found to determine PCSK9 expression as well as the extent of autophagy. In keeping with these data in mice, PCSK9 was also found to be highly expressed in the ischaemic myocardium mostly in the border zones. The expression of both LC3 and beclin-1 (markers of apoptosis) in LDLr−/− cardiomyocytes in response to mouse recombinant PCSK9 was much less than in wild-type mice cardiomyocytes, indicating that the effects of PCSK9 in the ischaemic heart were dependent on LDLr expression. These concepts are partly summarized in Figure 4.
It is conceivable that targeted therapy against PCSK9 may have improved cardiac outcome in clinical trials in patients with acute and chronic ischaemia6–8 by altering some of the pro-inflammatory mechanisms discussed above.
9. PCSK9–LOX-1 interactions
LOX-1 is the primary SR for ox-LDL on ECs, and it is also expressed in macrophages, smooth muscle cells, and fibroblasts, especially when these cells are exposed to ox-LDL, angiotensin II or pro-inflammatory cytokines. Of note, LOX-1 is also highly expressed in the growing plaque as well as in the rupture-prone plaque.46,47 LOX-1 is a well-established mediator of inflammation and atherosclerosis.14–16 Studies from our laboratory using LOX-1 gene deletion mice show a marked decrease in atherosclerosis in LDLr knockout mice fed a high fat diet.47 LOX-1 deletion was associated with a significant decrease in inflammatory cell accumulation in the vascular wall. On the other hand, endothelial overexpression of LOX-1 has been shown to increases plaque formation and increase in atherosclerosis.34 LOX-1 is also highly expressed in the ischaemic hearts and contributes to the development of inflammation and cardiomyocyte apoptosis.48 Blockade with a monoclonal antibody or gene deletion have shown amelioration of inflammation, reduction in apoptosis and infarct size, and improvement in cardiac contractile function in rodents subjected to coronary artery occlusion.49,50
Similar to LOX-1, PCSK9 can also be activated by LPS and pro-inflammatory cytokines, and plays a key role in ECs, VSMCs,25 and macrophages.18 Studies have shown a positive feedback between PCSK9 and LOX-1 exists in VSMCs, wherein LOX-1 activation stimulates PCSK9 expression.25 Reciprocally, PCSK9 promotes LOX-1 expression, uptake of ox-LDL and thus it induces a pro-inflammatory state. Both PCSK9 and LOX-1 share many of the same signalling pathways leading to intravascular inflammation and cellular apoptosis. Recent studies show an interplay between LOX-1 and PCSK9 as a feedback loop, mediated through NADPH oxidase activation. Data obtained in both in vitro and in vivo settings provide a compelling evidence for the activation of PCSK9-LOX-1 axis mediated principally via altered ROS generation while the fluid shear forces change along the length of arterial channel.26 Pathologic studies have indeed shown co-expression of LOX-1 and PCSK9 in atherosclerotic plaque.25
10. Conclusion
PCSK9 is expressed in atherosclerotic regions and in the ischaemic hearts. It possibly exerts pro-atherogenic effects through its pro-inflammatory effects. The effects of PCSK9 are largely LDLr-dependent. Evidence points to the role of PCSK9 in SR expression, ox-LDL uptake, foam cell formation and neo-intima proliferation. A positive feedback loop between SRs such as LOX-1 and PCSK9 leads to generation of mtROS, potentiation of cellular injury, culminating in cell death. The central role of PCSK9 in inflammatory pathways of atherosclerosis is depicted in Figure 5. Recent studies pointing to expression of PCSK9 in border zones of infarct also suggest a possible role of PCSK9 in infarct extension and expansion via induction of apoptosis and autophagy. Targeted therapy against PCSK9, possibly along with inhibitors of other mediators of inflammation, could thus present potent therapeutic options to reduce ASCVD burden, beyond the benefit achieved with LDL-C lowering. Given the prospect of PCSK9 modulators to alter approaches to cardiovascular disease, we appreciate a model whereby a secreted plasma protein, whose action can be easily inhibited, renders dominant control over lipoprotein metabolism as well as inflammation.51,52
Schematic diagram of the pathways by which PCSK9 may regulate atherogenesis through LOX-1 response. Circulating PCSK9 regulates LDL concentration in the blood. LDL contains plentiful unsaturated fatty acid and is prone to be oxidized to ox-LDL. As the major receptor of ox-LDL on the surface of vascular cells, LOX-1 plays a key role in the development of atherosclerosis. PCSK9 interacts with LOX-1 via many signalling pathways, such as damaged mitochondrial DNA (mtDNA), ROS, NADPH, NF-κB, MAPK, or VCAM-1. The interaction between PCSK9 and LOX-1 regulates foam cells formation and cell apoptosis, and further determines atherogenesis.
Conflict of interest: none declared.
Funding
This study was supported by the National Natural Science Foundation of China (11572028, 11421202) and National Key Research and Development Program in China (2016YFC1101100). Additional support was provided by Grants-in-Aid from the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development, Washington, DC (BX-000282-05).
References
Author notes
Zufeng Ding and Naga Venkata K. Pothineni contributed equally and thus be considered as co-first authors.
