The central role of arterial retention of cholesterol-rich apolipoprotein-B-containing lipoproteins in the pathogenesis of atherosclerosis: a triumph of simplicity

Borén, Jan; Williams, Kevin Jon

doi: 10.1097/MOL.0000000000000330
ATHEROSCLEROSIS: CELL BIOLOGY AND LIPOPROTEINS Edited by Andrew Newby and Mohamad Navab

Purpose of review: Today, it is no longer a hypothesis, but an established fact, that increased plasma concentrations of cholesterol-rich apolipoprotein-B (apoB)-containing lipoproteins are causatively linked to atherosclerotic cardiovascular disease (ASCVD) and that lowering plasma LDL concentrations reduces cardiovascular events in humans. Here, we review evidence behind this assertion, with an emphasis on recent studies supporting the ‘response-to-retention’ model – namely, that the key initiating event in atherogenesis is the retention, or trapping, of cholesterol-rich apoB-containing lipoproteins within the arterial wall.

Recent findings: New clinical trials have shown that ezetimibe and anti-PCSK9 antibodies – both nonstatins – lower ASCVD events, and they do so to the same extent as would be expected from comparable plasma LDL lowering by a statin. These studies demonstrate beyond any doubt the causal role of apoB-containing lipoproteins in atherogenesis. In addition, recent laboratory experimentation and human Mendelian randomization studies have revealed novel information about the critical role of apoB-containing lipoproteins in atherogenesis. New information has also emerged on mechanisms for the accumulation in plasma of harmful cholesterol-rich and triglyceride-rich apoB-containing remnant lipoproteins in states of overnutrition. Like LDL, these harmful cholesterol-rich and triglyceride-rich apoB-containing remnant lipoprotein remnants become retained and modified within the arterial wall, causing atherosclerosis.

Summary: LDL and other cholesterol-rich, apoB-containing lipoproteins, once they become retained and modified within the arterial wall, cause atherosclerosis. This simple, robust pathophysiologic understanding may finally allow us to eradicate ASCVD, the leading killer in the world.

aDepartment of Molecular and Clinical Medicine, University of Gothenburg

bSahlgrenska University Hospital, Gothenburg, Sweden

cSection of Endocrinology, Diabetes, & Metabolism, Department of Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA

Correspondence to Jan Borén, MD, PhD, Wallenberg Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden. Tel: +46 733 764264; e-mail: jan.boren@wlab.gu.se

This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0,where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by/4.0

Article Outline
Back to Top | Article Outline

INTRODUCTION

Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death globally. Widespread in developed areas of the world and now becoming more common in poorer countries, deaths from ASCVD are projected to increase to more than 2.3 × 107 per year by 2030. It is tempting to think of atherosclerosis as a disease of the modern lifestyle. Yet atherosclerosis has plagued humans for thousands of years and has been detected in 4000-year-old Egyptian mummies.

Today, it is no longer a hypothesis, but an established fact, that increased plasma concentrations of cholesterol-rich apolipoprotein-B (apoB)-containing lipoproteins are causatively linked to ASCVD and that lowering LDL concentrations with statins and nonstatins reduces atherosclerotic cardiovascular events in humans [1,2▪▪–4▪▪,5▪,6▪]. Despite the clarity of the evidence today, the role of LDL was questioned and even ridiculed for many years [7]. During that period, numerous competing hypotheses [8–11] were articulated to explain the initiating events in atherogenesis. After decades of research, however, there is now a large body of evidence to support the ‘response-to-retention hypothesis – namely, that the key initiating event in atherogenesis is the retention, or trapping, of cholesterol-rich apoB-containing lipoproteins within the arterial wall. The retained lipoproteins and their byproducts provoke a series of strikingly maladaptive local responses that cause plaque initiation, growth, and evolution (Fig. 1).

Modern research on atherosclerosis began with the insightful and pioneering ‘cholesterol hypothesis’ of Anichkov and Khalatov [12,13]. As a point of clarification, however, we now know that many things that carry cholesterol near arteries – such as normal HDL and erythrocytes (which transport a similar amount of cholesterol in blood as LDL does) – do not cause atherosclerosis. Thus, cholesterol per se is not the cause of this disease. In contrast, cholesterol-rich apoB-lipoproteins possess special properties that render them uniquely pathogenic in ASCVD.

Back to Top | Article Outline

The response-to-retention hypothesis of atherogenesis

The response-to-retention hypothesis drew on work from the 1940s to the 1980s showing that lipoproteins can interact with proteoglycans of the arterial wall [14–17]. Lipids and apoB accumulate at lesion-prone sites before gross morphological changes occur [18–21], and retention of apoB-lipoproteins is seen throughout the progression of atherosclerosis. The consequences of the retention of apoB-lipoproteins include, not only an accumulation of lipid, but also prolonged exposure of these particles to local enzymes and other factors within the vessel wall. The retained and modified apoB-lipoproteins trigger cellular responses within the artery wall that accelerate further lipoprotein retention and lesion development [9,11,22].

Back to Top | Article Outline

Influx of apolipoprotein-B-lipoproteins into the artery wall

Lipoproteins normally flux into and out of the arterial wall [20,23]. The molecular mediators of this transendothelial movement of lipoproteins remain incompletely characterized. Recent evidence has suggested roles for caveolin-1 [24,25] and the scavenger receptor class B type I (SR-BI) [26], but additional mediators are likely [27].

ApoB-lipoproteins up to only approximately 70 nm in diameter [i.e., chylomicron remnants, smaller VLDL, IDL, LDL, and lipoprotein(a)] can efficiently cross an intact endothelium, and among these, the smaller ones pass more readily than the larger ones [23]. This size limitation explains why patients with lipoprotein lipase deficiency do not develop atherosclerosis despite very high plasma levels of large apoB-containing chylomicrons.

Studies in-vivo of the influx and egress of LDL particles into and out of the arterial intima have shown that, although the endothelial layer remains intact over most atherosclerotic lesions, its permeability to LDL becomes abnormally high [20,28,29]. The precise stimuli and molecular mechanism(s) responsible for this increased permeability are still not elucidated, and it was not known until recently if the increased endothelial permeability for LDL could be reversed. To examine this issue, Bartels et al.[30▪▪] fed LDL receptor null (Ldlr−/−) mice on a high-cholesterol diet for up to 5 months to increase their plasma concentrations of apoB-lipoproteins, thereby provoking the formation of atherosclerotic plaques. To investigate the effect of an abrupt lowering of plasma apoB-lipoprotein concentrations on aortic endothelial permeability to LDL and the fractional degradation rates of apoB-lipoproteins within the atherosclerotic lesions, these authors used an anti-apoB antisense oligonucleotide (ASO) to reduce hepatic apoB synthesis. Concentrations of apoB-containing lipoproteins in plasma fell sharply to nearly undetectable levels within 3 days after administration of the ASO. The authors then analyzed the aortic plaques after 1 or 4 weeks of ASO treatments. Lowering of plasma apoB-lipoprotein concentrations reduced LDL permeability into the arterial wall within 1 week of ASO treatment, and this effect preceded any detectable changes in the cellular composition or size of the atherosclerotic lesions [30▪▪]. The molecular mechanisms involved still remain unclear, and effects on caveolin-1 and SR-BI were not examined. Bartels et al.[30▪▪] ruled out a nonspecific process by showing that the anti-apoB ASO treatment had no effect on endothelial permeability to Evans blue dye. In addition, correction of the hypercholesterolemia caused the fractional degradation rates of apoB within the plaques to fall sharply. Most importantly, the rapid decreases in permeability to LDL and in the fractional degradation of LDL that enters the plaque may turn out to be crucial for subsequent plaque stabilization and atherosclerosis regression [6▪].

Back to Top | Article Outline

Retention of atherogenic apolipoprotein-B-lipoproteins within the artery wall as the key pathogenic event in atherosclerosis

Because the capacity of transendothelial transport is high even in normal arterial segments, it is unlikely that influx of LDL and other smaller apoB-lipoproteins from the bloodstream is rate limiting in determining their concentrations within the artery wall. Instead, mechanisms for the selective retention of a tiny percentage of the apoB-lipoproteins that enter the artery wall drive their local accumulation and hence atherogenesis. Support for this model came from early work by Schwenke and Carew showing that LDL entry did not differ between normal arterial sites that are susceptible versus resistant to subsequent plaque development. Although the same amount of LDL entered, the susceptible sites, though healthy, already showed greater LDL accumulation [20]. More recent support comes from molecular studies by Tran-Lundmark et al. who crossed glycosaminoglycan (GAG)-deficient perlecan (Hspg2Δ3/Δ3) mice with hypercholesterolemic apolipoprotein-E (apoE)-null (Apoe−/−) mice. Because perlecan participates both as a permeability barrier and as a proretentive molecule within the murine arterial wall, the influx of LDL and other apoB-lipoproteins into the aortic wall in vivo was increased in Hspg2Δ3/Δ3/Apoe−/− mice compared with Apoe−/− controls, whereas subendothelial retention of LDL was paradoxically lower. In other words, this ingenious genetic manipulation of perlecan separated the two processes. Importantly, these authors demonstrated a significant reduction of atherosclerotic lesions in Hspg2Δ3/Δ3/Apoe−/− mice compared with Apoe−/− controls, indicating the key role of decreased apoB-lipoprotein retention regardless of the increase in endothelial permeability to LDL entry. Thus, most apoB-lipoprotein particles that entered the arterial wall left without contributing to the growth of the atherosclerotic lesion [31].

In earliest atherogenesis, negatively charged proteoglycans in the extracellular matrix of the arterial intima bind and trap apoB-lipoproteins via electrostatic interactions with specific positively charged aminoacyl residues in the full-length hepatic form of apoB, apoB100 (residues 3359–3369) [32], and in the truncated intestinal form, apoB48 (residues 84–94) [33]. Moreover, apoB48-lipoproteins typically contain numerous molecules of apoE, an apoprotein that has a proteoglycan-binding domain almost identical to the proteoglycan-binding sequence in apoB100. Proteoglycans are negatively charged due to the sulfate and carboxylic acid groups in their GAG side-chains. In experimental studies, several arterial-wall proteoglycans have been shown to be important for apoB-lipoprotein retention and atherosclerosis, most notably the matrix-associated proteoglycans biglycan, perlecan, and versican [9,34,35].

Consistent with the response-to-retention model, numerous other interventions have been performed that do not change plasma concentrations of apoB-lipoproteins in hypercholesterolemic animals but specifically decrease or increase the retention of these particles within the arterial wall. These interventions correspondingly decrease or increase atherogenesis. Such interventions include mutagenesis of the proteoglycan/GAG-binding domain of apoB100, thereby slowing LDL retention and atherogenesis [36], manipulations of arterial matrix to alter its affinity for apoB [31,37–39,40▪▪,41▪], and knockouts of arterial-wall enzymes specifically implicated in apoB-lipoprotein retention and aggregation [42–45].

The first of these studies, which used mutagenesis of apoB100 to block its direct adherence to arterial matrix, emphasizes the importance of LDL quality, as opposed to simply focusing on its concentrations in plasma. Other variations in LDL quality may also affect its atherogenicity, such as surface lipid composition [46] and core lipid composition (which influences the conformation of apoB and hence its interactions with proteoglycans) [47,48▪▪,49]. In addition, the protein composition of apoB-lipoproteins influences their interactions with proteoglycans. As discussed above, apoE mediates binding of lipoproteins to arterial GAGs, although apoE also facilitates hepatic disposal of atherogenic lipoproteins. In contrast, the small exchangeable apolipoprotein, apolipoprotein-C (apoC)-III, increases the affinity of LDL for arterial-wall proteoglycans, whereas decreasing hepatic uptake of apoB-lipoproteins [50], thereby increasing the accumulation of atherogenic lipoproteins within the vessel wall [51,52]. The mechanism has been unclear because apoC-III by itself lacks positively charged domains to bind arterial-wall proteoglycans [51]. Hiukka et al.[53] demonstrated that an increased apoCIII : apoB molar ratio in LDL isolated from patients with type 2 diabetes correlated with lower contents of unesterified cholesterol, sphingomyelin, ceramide, and GM1. Importantly, this combination of compositional changes was associated with increased proteoglycan binding [53]. The mechanism remains unclear but one possibility is that a more fluid monolayer on the LDL particle surface may facilitate the insertion of more molecules of apoC-III and permit conformational changes in apoB100 that increase its proteoglycan-binding affinity. In contrast, however, the apoCIII : apoB ratio in LDL from nondiabetic control patients showed no correlations with the content of these lipids, indicating less global changes in LDL composition [53].

Regarding the subendothelial arterial matrix, recent work has implicated proteases [54] and other factors [55,56▪] in the regulation of the arterial-wall content of LDL-binding proteoglycans and hence atherosclerosis. She et al.[40▪▪,41▪] recently focused on a less well known proteoglycan in the vasculature, the neural/glia antigen 2 (NG2) proteoglycan. Although NG2 is undetectable in the intima of normal murine arteries, early atheromata in Apoe−/− mice contain immature synthetic smooth muscle cells (s-SMCs) that express NG2 [40▪▪]. Thus, the atherogenic effects of NG2 seem to emerge with accumulation of s-SMCs [21,57]. She et al. also demonstrated a remarkable role for NG2-positive s-SMCs in trapping LDL and then presenting it to macrophages. It is a novel mechanism for the presentation of undesirable material to macrophages that, we speculate, may have evolved to facilitate the disposal of certain infectious agents or cellular debris [58,59]. In the context of retained apoB-lipoproteins, however, the process becomes maladaptive. Thus, NG2-positive s-SMCs dramatically increase the uptake of LDL by macrophages within the arterial wall, promoting foam-cell formation, whereas NG2-deficient s-SMCs reduce LDL uptake. Despite worse obesity and worse hyperlipidemia, double knockout mice (Ng2−/−/Apoe−/−) developed less atherosclerosis than did Apoe−/− controls. Surprisingly, the NG2 GAG chains were not required for the binding of LDL to NG2 [40▪▪]. Furthermore, NG2 also bound acetylated LDL, indicating that NG2 has the capacity to bind LDL through hydrophobic interactions. These features make NG2 unique amongst LDL-binding proteoglycans [40▪▪] and may be related to its normal biologic functions.

Why does atherosclerosis preferentially develop at specific sites in the arterial tree? These sites are often associated with branches and bifurcations, which expose the endothelium to disturbed laminar blood flow and shear stress [60]. Most conventional explanations for increased atherosclerosis susceptibility at these sites have focused on biomechanical alterations of endothelial cells, such as increased permeability and elaboration of cytokines [61], but none of these proposed mechanisms has been definitely demonstrated. In a recent advance, Steffensen et al. showed that induction of disturbed laminar flow in the straight segment of the otherwise atherosclerosis-resistant common carotid artery of mice provokes matrix proliferation in the nearby arterial wall, transforming it into a lipoprotein-retaining site – but without altering LDL influx. This provides experimental evidence for a causal chain linking disturbed laminar flow patterns to increased arterial matrix deposition, apoB-lipoprotein retention, and atherosclerosis [62▪▪]. Like the prior work cited above [20,31], this study contradicts the notion of a key role for disturbed endothelial permeability to LDL in early phases of atherogenesis. Unraveling the molecular mechanisms from disturbed flow to matrix proliferation and increased lipoprotein retention will be a fruitful area for future research.

New work has focused on apoB-lipoprotein retention as a potential therapeutic target. One strategy is the creation of mAbs that block apoB-binding sites on GAG chains within the arterial matrix [63,64▪]. Interestingly, the antigen-binding site (the CDR3 of the heavy chain) of one of these antibodies contains an arginine motif that resembles the major GAG-binding sequence in apoB100[33,36,64▪]. The antibodies decrease intra-arterial lipoprotein retention and hence the progression of atherosclerosis in hypercholesterolemic Apoe−/− mice [63,64▪].

Back to Top | Article Outline

Cholesterol-rich and triglyceride-rich apolipoprotein-B-containing remnant lipoproteins, which are metabolically distinct from LDL, have emerged as a major driver of human atherosclerosis

Lipid and lipoprotein concentrations are often assessed in fasting plasma, but the idea that particles originating in the postprandial state may contribute to atherosclerosis appeared in the literature at least as far back as the 1940s [65,66]. In that era, however, the overwhelming driver of human atherosclerosis was LDL, which is not primarily a postprandial particle.

The situation has changed dramatically since then. With the rise of overnutrition, obesity, and the atherometabolic syndrome, harmful cholesterol-rich and triglyceride-rich apoB-containing remnant lipoproteins (C-TRLs) have emerged as a major driver of human ASCVD worldwide [67▪]. The characteristic dyslipoproteinemia of the atherometabolic syndrome increases plasma concentrations of C-TRL remnants, not LDL. The major defect is impaired hepatic removal of C-TRLs from plasma [68▪]. Like LDL [9], C-TRL remnants become retained within the arterial wall [6▪,11,33,69]. Mendelian randomization studies have clearly demonstrated their causal role in human ASCVD events [70]. Of note, each C-TRL particle contains up to 40 times more cholesterol compared with an LDL particle. Unfortunately, patients treated with optimal statin therapy [71] and even PCSK9 inhibitors [3▪▪,4▪▪] exhibit considerable residual risk for ASCVD events, which may occur, in large part, because these agents lower fasting or postprandial C-TRL levels by only 4–25% [72–74]. There is therefore a need to find new therapeutic approaches to restore normal, rapid hepatic removal of C-TRLs from plasma, to lower residual ASCVD risk in obesity, the atherometabolic syndrome, and type 2 diabetes.

Back to Top | Article Outline

Aggregation and modifications of retained apolipoprotein-B-lipoproteins within the artery wall

Following retention of cholesterol-rich apoB-lipoproteins within the artery wall, the lipoproteins have been shown to undergo several modifications with important biological consequences. For example, proteoglycan-bound LDL in vitro forms aggregates that resemble material seen in vivo, and retained lipoproteins are more susceptible to further modifications. Key enzymes implicated in apoB-lipoprotein retention, aggregation, and atherogenesis include the secretory sphingomyelinase (S-SMase), lipoprotein lipase, and the nonpancreatic secretory group V phospholipase-A2 (PLA2-V) [9,42–45,75] (Fig. 1). These enzymes, particularly lipoprotein lipase, bridge between LDL and proteoglycans independently of the physical state of apoB and thereby cause a shift in the retentive mechanism from a low-affinity process (apoB-GAG binding) in the pristine arterial wall to a high-affinity process (lipoprotein-GAG binding) in an established atheroma. This shift in retentive mechanism has direct clinical consequences: a lifetime plasma LDL cholesterol concentration of 80 mg/dl almost always protects from atherosclerosis [76] but pre-existing plaques grow if the LDL-cholesterol is ∼80 mg/dl [77].

Acidity in deeper parts of normal intima and within atherosclerotic plaques enhances lipolytic, proteolytic, and other modifications of apoB-containing lipoproteins that strongly increase their affinity for proteoglycans and may therefore accelerate their retention and the ensuing maladaptive cellular responses in the arterial intima [78▪]. In a fascinating advance, Sneck et al. elucidated the mechanism for SMase-induced aggregation of LDL. The enzyme induces a massive, global conformational change in apoB that exposes hydrophobic motifs that apparently adhere from one digested LDL particle to the next [79].

Several lines of evidence implicate aggregation of apoB-lipoproteins within the arterial wall as a major accelerator of lipoprotein retention and atherogenesis. Once LDL and other apoB-lipoproteins in the arterial wall have aggregated, diffusion back into plasma becomes essentially impossible, due to the large size of the aggregates and their greatly enhanced affinity as multivalent ligands for arterial matrix, as well as conformational changes that expose additional positively charged domains on apoB. Lipid hydrolysis and other modifications of the retained, aggregated lipoproteins release biologically active byproducts that recruit macrophages and other cells into the developing lesion, while also blocking their emigration, thereby accelerating disease progression (Fig. 1; recently reviewed in [80]).

Ruuth et al.[46] recently demonstrated that susceptibility of plasma LDL to aggregation upon exposure to SMase ex vivo varies considerably amongst human patients, predicts future deaths from ASCVD, and can be altered by diet. This work adds to a growing body of data implicating SMase in human atherosclerosis [9,75]. Crucially, the work identifies LDL aggregability in the presence of SMase as a new, potentially modifiable cardiovascular risk factor. Aggregation-prone LDL – dubbed ‘unstable’ LDL – exhibits several compositional characteristics, including an increased sphingomyelin : phosphatidylcholine (SM : PC) ratio [46]. Interestingly, an increase in dietary polyunsaturated fatty acids and fiber decreased the SM : PC ratio and stabilized LDL, whereas an increase in dietary sucrose caused the opposite. Consistent with these findings, a diet rich in saturated fats has been shown to increase serum SMase activity and, consequently, increase LDL aggregation in mice [81]. These results further emphasize the importance of LDL quality in human ASCVD. Moreover, measurement of LDL instability in the presence of SMase may serve as a predictive biomarker for the identification of patients at unrecognized risk of cardiovascular death who might benefit from specific, targeted interventions.

Back to Top | Article Outline

Retained lipoproteins induce maladaptive cellular responses in the arterial wall that accelerate further apolipoprotein-B-lipoprotein retention

Retained and aggregated lipoproteins provoke a series of local biological responses that eventually include a maladaptive reaction dominated by abnormally persistent macrophages and T cells that accelerate lipoprotein retention and other features of plaque development (Fig. 1). Aggregated apoB-lipoproteins are avidly taken up by macrophages [9,82] and by vascular SMCs [83] leading to foam-cell formation. These processes stimulate the release of proatherogenic factors that induce the synthesis of proteoglycans with enhanced affinity for atherogenic lipoproteins [9,82]. In addition, monocyte/macrophages recruited into atheromata secrete proretentive enzymes, notably lipoprotein lipase, sphingomyelinase, and PLA2, that accelerate further retention of atherogenic lipoproteins. In addition, persistent macrophages in atherosclerotic plaques secrete proteases that weaken the overlying fibrous cap, and these cells release tissue factor, a potent procoagulant. These maladaptive responses favor plaque rupture, robust clot formation that often occludes the arterial lumen, and downstream ischemia (Fig. 1).

A critical question is why retained apoB-lipoproteins induce this abnormal persistence of macrophages and T cells? It has been hypothesized that specific cellular and molecular programs that cause immune cells to remain in place may have evolved as a defense against Mycobacterium tuberculosis, an acid-fast bacillus that is not killed after phagocytosis and would therefore be spread throughout the body by emigrating macrophages. Interestingly, retained and modified apoB-containing lipoproteins within the arterial wall elicit many of the same antiemigration signals as M. tuberculosis does [6▪,11,84–86]. Unfortunately, the result is a crippling of the reticuloendothelial system, which otherwise has a huge capacity that could easily handle a few grams of intramural cholesterol and other debris.

Back to Top | Article Outline

New data regarding possible roles for HDL in the response-to-retention model of atherogenesis

The pathogenic importance in atherosclerosis of plasma HDL-cholesterol (HDL-C) levels has come into doubt, due to recent failures of clinical trials of agents that raise plasma HDL-C concentrations [87,88] and the lack of ASCVD protection from human gene polymorphisms that raise plasma concentrations of HDL-C [89]. In animal models, however, injections of HDL, overexpression of apoA-I, and strategies to enhance HDL function delay atherosclerosis progression and even promote plaque stabilization and regression [11,85,88]. In the context of the response-to-retention hypothesis, roles for HDL in every step have been hypothesized [87] – namely, interfering with the irreversible binding of plasma LDL to arterial wall proteoglycans [90–92], blocking SMase-induced aggregation of LDL [79,93], removing toxic lipids, and resolving the maladaptive inflammatory infiltrate [94–98]. Along these lines, the apoA-I mimetic peptide 4F was recently shown to block SMase-induced LDL aggregation and the increase in binding of the modified LDL particles to human aortic proteoglycans [99▪]. In contrast, abnormal HDL or apoA-I within the arterial wall may have adverse effects [96,100,101▪,102].

Back to Top | Article Outline

Atherogenicity of apolipoprotein-B-lipoproteins

Based on our present understanding for how cholesterol-rich apoB-lipoproteins induce atherosclerosis, the atherogenicity of apoB-containing lipoproteins may depend on

1. Their plasma concentrations, because high levels of circulating apoB-lipoproteins increase the probability that these particles will enter and be retained in the subendothelium.

2. Their ability to become retained in the artery wall. This is influenced by their size (<70 nm) and their affinity for arterial-wall proteoglycans. The affinity is modulated by the lipid and protein composition of the lipoprotein particles. In particular, apoC-III on LDL increases its proteoglycan binding.

3. The instability of retained lipoproteins, that is, how readily they aggregate in the presence of arterial-wall enzymes, particularly S-SMase. This property has been linked to LDL lipid composition and is affected by diet.

4. The susceptibility of aggregated and retained lipoprotein to further modifications within the artery wall.

5. The ability of the modified lipoproteins to induce a maladaptive cellular response.

Thus, it can be hypothesized that patients with atherogenic apoB-lipoproteins characterized by high binding affinity to arterial proteoglycans, increased susceptibility to aggregate, and features that promote a hyperresponsive maladaptive cellular infiltrate may develop atherosclerosis despite only moderately elevated plasma levels of cholesterol. It remains to be demonstrated whether assessments of these specific qualities of LDL and C-TRLs will add predictive power beyond conventional risk factors or help identify groups of patients for targeted therapies.

Back to Top | Article Outline

Reclassification of risk factors for atherosclerosis into causative agents, exacerbators, and mere bystander phenomena

Our understanding of the pathogenesis of ASCVD is based on laboratory investigation, human epidemiology, genetic studies, and clinical trials. Collectively, these studies have demonstrated beyond any doubt that cholesterol-rich apoB-lipoproteins are causally linked to atherogenesis and that lowering the plasma concentration of LDL is the most effective therapy to date against ASCVD. The critical step is that cholesterol-rich apoB-lipoproteins from plasma become pathogenic only after their retention within the arterial wall.

Using our extensive knowledge of the pathogenesis of atherosclerosis, we can now reclassify nearly all epidemiologic risk factors into causative agents, exacerbating factors, and bystander phenomena (Table 1) [80]. Causative and exacerbating factors are targets for therapy, bystander phenomena are not.

Back to Top | Article Outline

CONCLUSION

It is hard to unravel the root cause of a condition from an end-stage lesion. Atherosclerosis was no exception. For more than a century and a half, many theories had been articulated to explain how a normal artery becomes atherosclerotic. As a testament to the importance of this area, most of these theories were tested in clinical trials. As a consequence, it is now established that increased plasma concentrations of cholesterol-rich apoB-containing lipoproteins are causatively linked to ASCVD. Accordingly, the most effective therapies against atherothrombotic cardiovascular disease – LDL-lowering drugs – are based upon the principle that decreasing the concentration of apoB-lipoproteins in the circulaton decreases the probability that they will enter and be retained in the subendothelium. At this point, we know enough about the pathophysiology of atherosclerosis that eradication of this major killer has become a genuine possibility.

Back to Top | Article Outline

Acknowledgements

None.

Back to Top | Article Outline

Financial support and sponsorship

The authors acknowledge support from the Swedish Research Council (J.B.), Swedish Heart-Lung Foundation (J.B. and K.J.W.), ALF-medel Västra Götalandsregionen (J.B. and K.J.W.), and the Ruth and Yonatan Ben-Avraham Fund (K.J.W.).

Back to Top | Article Outline

Conflicts of interest

Dr Williams reports purchasing stock in Gemphire Therapeutics, Inc., a company focused on the treatment of dyslipidemias.

Back to Top | Article Outline

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as

▪ of special interest

▪▪ of outstanding interest

Back to Top | Article Outline

REFERENCES

1. Mihaylova B, Emberson J, Blackwell L, et al. Cholesterol Treatment Trialists (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012; 380:581–590.
2▪▪. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015; 372:2387–2397.

A seminal study demonstrating that a nonstatin, ezetimibe, that lowers plasma LDL levels decreases atherosclerotic cardiovascular disease (ASCVD) events in humans to exactly the same extent as would be expected from the same degree of LDL lowering from a statin.

3▪▪. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372:1489–1499.

Refs. [3▪▪,4▪▪] present initial data that another nonstatin, anti-PCSK9 antibodies, that substantially lowers plasma LDL levels substantially decreases ASCVD events in humans.

4▪▪. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372:1500–1509.

Refs. [3▪▪,4▪▪] present initial data that another nonstatin, anti-PCSK9 antibodies, that substantially lowers plasma LDL levels substantially decreases ASCVD events in humans.

5▪. Hegele RA, Gidding SS, Ginsberg HN, et al. Nonstatin low-density lipoprotein—lowering therapy and cardiovascular risk reduction—statement from ATVB Council. Arterioscler Thromb Vasc Biol 2015; 35:2269–2280.

An important overview of historical and recent data that LDL lowering by nonstatins decreases ASCVD events in humans.

6▪. Williams KJ, Tabas I, Fisher EA. How an artery heals. Circ Res 2015; 117:909–913.

A commentary on Bartels ED, Christoffersen C, et al. 2015 (reference [30▪▪]).

7. Steinberg D. Thematic review series: the pathogenesis of atherosclerosis. An interpretive history of the cholesterol controversy: Part I. J Lipid Res 2004; 45:1583–1593.
8. Capron L. Pathogenie de l’atherosclerose: mises à jour des trois theories dominantes. Ann Cardiol Angeiol (Paris) 1989; 38:631–634.
9. Williams KJ, Tabas I. The response-to-retention hypothesis of early atherogenesis. Arterioscler Thromb Vasc Biol 1995; 15:551–561.
10. Ventura HO. Profiles in cardiology. Rudolph Virchow and cellular pathology. Clin Cardiol 2000; 23:550–552.
11. Williams KJ, Tabas I. Lipoprotein retention – and clues for atheroma regression. Arterioscler Thromb Vasc Biol 2005; 25:1536–1540.
12. Anitschkow N, Chalatow S. Über experimentelle Cholesterinsteatose und ihre Bedeutung für die Entstehung einiger pathologischer Prozesse. Zentrbl Allg Pathol Pathol Anat 1913; 24:1–9.
13. Konstantinov IE, Mejevoi N, Anichkov NM, Nikolai N. Anichkov and his theory of atherosclerosis. Tex Heart Inst J 2006; 33:417–423.
14. Faber M. The human aorta; sulfate-containing polyuronides and the deposition of cholesterol. Arch Pathol (Chic) 1949; 48:342–350.
15. Camejo G, Lopez A, Vegas H, Paoli H. The participation of aortic proteins in the formation of complexes between low density lipoproteins and intima-media extracts. Atherosclerosis 1975; 21:77–91.
16. Iverius P-H. The interaction between human plasma lipoproteins and connective tissue glycosaminoglycans. J Biol Chem 1972; 247:2607–2613.
17. Vijayagopal P, Srinivasan SR, Radhakrishnamurthy B, Berenson GS. Interaction of serum lipoproteins and a proteoglycan from bovine aorta. J Biol Chem 1981; 256:8234–8241.
18. Smith EB, Slater RS. Lipids and low density lipoproteins in intima in relation to its morphological characteristics. Ciba Found Symp 1973; 12:39–62.
19. Tamminen M, Mottino G, Qiao JH, et al. Ultrastructure of early lipid accumulation in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 1999; 19:847–853.
20. Schwenke DC, Carew TE. Initiation of atherosclerotic lesions in cholesterol-fed rabbits. II. Selective retention of LDL vs. selective increases in LDL permeability in susceptible sites of arteries. Arteriosclerosis 1989; 9:908–918.
21. Nakashima Y, Fujii H, Sumiyoshi S, et al. Early human atherosclerosis: accumulation of lipid and proteoglycans in intimal thickenings followed by macrophage infiltration. Arterioscler Thromb Vasc Biol 2007; 27:1159–1165.
22. Borén J, Gustafsson M, Skålén K, et al. Role of extracellular retention of low density lipoproteins in atherosclerosis. Curr Opin Lipidol 2000; 11:451–456.
23. Sloop CH, Dory L, Roheim PS. Interstitial fluid lipoproteins. J Lipid Res 1987; 28:225–237.
24. Frank PG, Pavlides S, Cheung MW, et al. Role of caveolin-1 in the regulation of lipoprotein metabolism. Am J Physiol Cell Physiol 2008; 295:C242–248.
25. Fernández-Hernando C, Yu J, Suárez Y, et al. Genetic evidence supporting a critical role of endothelial caveolin-1 during the progression of atherosclerosis. Cell Metab 2009; 10:48–54.
26. Armstrong SM, Sugiyama MG, Fung KY, et al. A novel assay uncovers an unexpected role for SR-BI in LDL transcytosis. Cardiovasc Res 2015; 108:268–277.
27. Kraehling JR, Rajagopal C, Sessa WC. Identification of novel mechanisms of LDL uptake into endothelium. Naunyn-Schmiedeberg's Arch Pharmacol 2014; 387 (Suppl 1):S12Presented at the 80th Annual meeting, Deutsche Gesellschaft für Experimentelle und Klinische Pharmakologie und Toxikologie e.V. [German Society for Experimental and Clinical Pharmacology and Toxicology (registered association)], 1–3 April 2014, Hannover, Germany.
28. Nielsen LB, Stender S, Jauhiainen M, Nordestgaard BG. Preferential influx and decreased fractional loss of lipoprotein(a) in atherosclerotic compared with nonlesioned rabbit aorta. J Clin Invest 1996; 98:563–571.
29. Nielsen LB, Gronholdt ML, Schroeder TV, et al. In vivo transfer of lipoprotein(a) into human atherosclerotic carotid arterial intima. Arterioscler Thromb Vasc Biol 1997; 17:905–911.
30▪▪. Bartels ED, Christoffersen C, Lindholm MW, Nielsen LB. Altered metabolism of LDL in the arterial wall precedes atherosclerosis regression. Circ Res 2015; 117:933–942.

The authors show that rapid lowering of plasma concentrations of cholesterol-rich apoB-lipoproteins decreases the permeability of the endothelium overlying atheromata to LDL and decreases the fractional degradation of LDL that enters the plaque. This finding may be important for our understanding of plaque stabilization and atherosclerosis regression.

31. Tran-Lundmark K, Tran PK, Paulsson-Berne G, et al. Heparan sulfate in perlecan promotes mouse atherosclerosis: roles in lipid permeability, lipid retention, and smooth muscle cell proliferation. Circ Res 2008; 103:43–52.
32. Borén J, Olin K, Lee I, et al. Identification of the principal proteoglycan-binding site in LDL. A single-point mutation in apo-B100 severely affects proteoglycan interaction without affecting LDL receptor binding. J Clin Invest 1998; 101:2658–2664.
33. Flood C, Gustafsson M, Richardson PE, et al. Identification of the proteoglycan binding site in apolipoprotein B48. J Biol Chem 2002; 277:32228–32233.
34. Camejo G, Fager G, Rosengren B, et al. Binding of low density lipoproteins by proteoglycans synthesized by proliferating and quiescent human arterial smooth muscle cells. J Biol Chem 1993; 268:14131–14137.
35. Tannock LR. Proteoglycan-LDL interactions: a novel therapeutic target? Atherosclerosis 2014; 233:232–233.
36. Skålén K, Gustafsson M, Rydberg EK, et al. Subendothelial retention of atherogenic lipoproteins in early atherosclerosis. Nature 2002; 417:750–754.
37. Vikramadithyan RK, Kako Y, Chen G, et al. Atherosclerosis in perlecan heterozygous mice. J Lipid Res 2004; 45:1806–1812.
38. Huang F, Thompson JC, Wilson PG, et al. Angiotensin II increases vascular proteoglycan content preceding and contributing to atherosclerosis development. J Lipid Res 2008; 49:521–530.
39. Tang T, Wilson PG, Thompson JC, et al. Prevention of TGFß induction attenuates angII-stimulated vascular biglycan and atherosclerosis in Ldlr−/− mice. J Lipid Res 2013; 54:2255–2264.
40▪▪. She ZG, Chang Y, Pang HB, et al. NG2 ablation reduces low-density lipoprotein retention of synthetic smooth muscle cells and atherogenesis. Arterioscler Thromb Vasc Biol 2016; 36:49–59.

The authors describe a novel role for NG2-positive s–smooth muscle cells in trapping LDL and then presenting this LDL to macrophages. Despite worse obesity and worse hyperlipidemia, double knockout mice (Ng2−/−/Apoe−/−) developed less atherosclerosis than did Apoe−/− controls. The authors show that NG2 has the capacity to bind LDL through hydrophobic interactions. These features make NG2 unique amongst LDL-binding proteoglycans and may be related to its normal function in the arterial intima.

41▪. Fogelstrand P, Borén J. Catch and release: NG2-coated vascular smooth muscle cells capture lipoproteins for macrophages. Arterioscler Thromb Vasc Biol 2016; 36:7–8.

A commentary on She et al. 2016 [40▪▪].

42. Bostrom MA, Boyanovsky BB, Jordan CT, et al. Group V secretory phospholipase A2 promotes atherosclerosis: evidence from genetically altered mice. Arterioscler Thromb Vasc Biol 2007; 27:600–606.
43. Öörni K, Kovanen PT. PLA2-V: a real player in atherogenesis. Arterioscler Thromb Vasc Biol 2007; 27:445–447.
44. Gustafsson M, Levin M, Skålén K, et al. Retention of low-density lipoprotein in atherosclerotic lesions of the mouse: evidence for a role of lipoprotein lipase. Circ Res 2007; 101:777–783.
45. Devlin CM, Leventhal AR, Kuriakose G, et al. Acid sphingomyelinase promotes lipoprotein retention within early atheromata and accelerates lesion progression. Arterioscler Thromb Vasc Biol 2008; 28:1723–1730.
46. Ruuth M, Nguyen SD, Vihervaara T, et al. Unstable LDL – novel mechanism of atherogenesis and link to cardiovascular deaths. 15 April 2016, Krogerup Højskole, Humlebæk, Denmark: Oral presentation at the 22nd annual Scandinavian atherosclerosis conference, Scandinavian Society for Atherosclerosis Research (SSAR); 2016.
47. Coronado-Gray A, van Antwerpen R. The physical state of the LDL core influences the conformation of apolipoprotein B-100 on the lipoprotein surface. FEBS Lett 2003; 533:21–24.
48▪▪. Melchior JT, Sawyer JK, Kelley KL, et al. LDL particle core enrichment in cholesteryl oleate increases proteoglycan binding and promotes atherosclerosis. J Lipid Res 2013; 54:2495–2503.

The authors tested the hypothesis that the increased atherosclerosis associated with LDL core enrichment in cholesteryl oleate results from an increased affinity of the LDL particle for arterial proteoglycans. Results strongly support their hypothesis. ‘This is an important observation when considering that monounsaturated fats such as olive oil are still being promoted as healthy and protective against heart disease’, state the authors.

49. Flood C, Gustafsson M, Pitas RE, et al. Molecular mechanism for changes in proteoglycan binding on compositional changes of the core and the surface of low-density lipoprotein-containing human apolipoprotein B100. Arterioscler Thromb Vasc Biol 2004; 24:564–570.
50. Borén J, Watts GF, Adiels M, et al. Kinetic and related determinants of plasma triglyceride concentration in abdominal obesity: multicenter tracer kinetic study. Arterioscler Thromb Vasc Biol 2015; 35:2218–2224.
51. Olin-Lewis K, Krauss RM, La Belle M, et al. ApoC-III content of apoB-containing lipoproteins is associated with binding to the vascular proteoglycan biglycan. J Lipid Res 2002; 43:1969–1977.
52. Davidsson P, Hulthe J, Fagerberg B, et al. A proteomic study of the apolipoproteins in LDL subclasses in patients with the metabolic syndrome and type 2 diabetes. J Lipid Res 2005; 46:1999–2006.
53. Hiukka A, Ståhlman M, Pettersson C, et al. ApoCIII-enriched LDL in type 2 diabetes displays altered lipid composition, increased susceptibility for sphingomyelinase, and increased binding to biglycan. Diabetes 2009; 58:2018–2026.
54. Didangelos A, Mayr U, Monaco C, Mayr M. Novel role of ADAMTS-5 in proteoglycan turnover and lipoprotein retention in atherosclerosis. J Biol Chem 2012; 287:19341–19345.
55. Seidelmann SB, Kuo C, Pleskac N, et al. Athsq1 is an atherosclerosis modifier locus with dramatic effects on lesion area and prominent accumulation of versican. Arterioscler Thromb Vasc Biol 2008; 28:2180–2186.
56▪. Tang T, Thompson JC, Wilson PG, et al. Biglycan deficiency: increased aortic aneurysm formation and lack of atheroprotection. J Mol Cell Cardiol 2014; 75:174–180.

Regulation of vascular proteoglycans seems to be coordinated because mice made genetically deficient in biglycan exhibit increased vascular perlecan content.

57. Nakashima Y, Wight TN, Sueishi K. Early atherosclerosis in humans: role of diffuse intimal thickening and extracellular matrix proteoglycans. Cardiovasc Res 2008; 79:14–23.
58. Maus F, Sakry D, Biname F, et al. The NG2 proteoglycan protects oligodendrocyte precursor cells against oxidative stress via interaction with OMI/HtrA2. PLoS One 2015; 10:e0137311.
59. Matsumoto H, Kumon Y, Watanabe H, et al. Accumulation of macrophage-like cells expressing NG2 proteoglycan and Iba1 in ischemic core of rat brain after transient middle cerebral artery occlusion. J Cereb Blood Flow Metab 2008; 28:149–163.
60. Peiffer V, Sherwin SJ, Weinberg PD. Does low and oscillatory wall shear stress correlate spatially with early atherosclerosis? A systematic review. Cardiovasc Res 2013; 99:242–250.
61. Kwak BR, Bäck M, Bochaton-Piallat ML, et al. Biomechanical factors in atherosclerosis: mechanisms and clinical implications. Eur Heart J 2014; 35:3013–3020.[ESC Position Paper].
62▪▪. Steffensen LB, Mortensen MB, Kjolby M, et al. Disturbed laminar blood flow vastly augments lipoprotein retention in the artery wall: a key mechanism distinguishing susceptible from resistant sites. Arterioscler Thromb Vasc Biol 2015; 35:1928–1935.

The authors provide experimental evidence for a causal chain linking disturbed laminar flow patterns to increased arterial matrix deposition and then increased apoB-lipoprotein retention and atherosclerosis. This study contradicts the notion of a key role for disturbed endothelial permeability to LDL in early phases of atherogenesis.

63. Brito V, Mellal K, Portelance SG, et al. Induction of antianti-idiotype antibodies against sulfated glycosaminoglycans reduces atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol 2012; 32:2847–2854.
64▪. Delgado-Roche L, Brito V, Acosta E, et al. Arresting progressive atherosclerosis by immunization with an antiglycosaminoglycan monoclonal antibody in apolipoprotein E-deficient mice. Free Radic Biol Med 2015; 89:557–566.

The authors have earlier reported the preventive antiatherogenic properties of an antichondroitin sulfate antibody response. Results in this study further demonstrate the use of this antiglycosaminoglycan antibody-based immunotherapy as a novel approach to target apoB-lipoprotein retention, and hence atherosclerosis, at different phases of progression.

65. Moreton JR. Atherosclerosis and alimentary hyperlipemia. Science 1947; 106:190–191.
66. Zilversmit DB. Atherogenesis: a postprandial phenomenon. Circulation 1979; 60:473–485.
67▪. Williams KJ, Wu X. Imbalanced insulin action in chronic over nutrition: clinical harm, molecular mechanisms, and a way forward. Atherosclerosis 2016; 247:225–282.

A comprehensive overview of imbalanced insulin action, also known as pathway-selective insulin resistance and responsiveness, in the pathogenesis of the atherometabolic syndrome and type 2 diabetes mellitus, including the characteristic dyslipoproteinemia and accelerated ASCVD risk in these disorders.

68▪. Taskinen MR, Borén J. New insights into the pathophysiology of dyslipidemia in type 2 diabetes. Atherosclerosis 2015; 239:483–495.

A review of kinetic studies of dyslipoproteinemia in the atherometabolic syndrome, implicating overproduction of cholesterol-rich and triglyceride-rich apoB-containing remnant lipoproteins but more importantly an impairment in their clearance from the circulation by the liver.

69. Williams KJ, Chen K. Recent insights into factors affecting remnant lipoprotein uptake. Curr Opin Lipidol 2010; 21:218–228.
70. Varbo A, Benn M, Tybjærg-Hansen A, et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013; 61:427–436.
71. Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008; 359:2195–2207.
72. Hassing HC, Mooij H, Guo S, et al. Inhibition of hepatic sulfatase-2 in vivo: a novel strategy to correct diabetic dyslipidemia. Hepatology 2012; 55:1746–1753.
73. Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med 2014; 370:1809–1819.
74. Holman RR, Koren MJ, Roth E, et al. Evaluation of the glycemic effects and efficacy and safety of evolocumab (AMG 145) in subjects with or without dysglycemia or metabolic syndrome. Diabetes 2015; 64 (suppl. 1):A68Oral presentation at the 75th Scientific Sessions of the American Diabetes Association, Chicago, IL, USA, 7 June 2015.
75. Tabas I, Li Y, Brocia RW, et al. Lipoprotein lipase and sphingomyelinase synergistically enhance the association of atherogenic lipoproteins with smooth muscle cells and extracellular matrix. A possible mechanism for low density lipoprotein and lipoprotein(a) retention and macrophage foam cell formation. J Biol Chem 1993; 268:20419–20432.
76. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006; 354:1264–1272.
77. Nissen SE, Tardif JC, Nicholls SJ, et al. Effect of torcetrapib on the progression of coronary atherosclerosis. N Engl J Med 2007; 356:1304–1316.
78▪. Öörni K, Rajamäki K, Nguyen SD, et al. Acidification of the intimal fluid: the perfect storm for atherogenesis. J Lipid Res 2015; 56:203–214.

In this review, the authors summarize the effects of acidic extracellular pH on atherogenesis, focusing on subendothelial retention of apoB-containing lipoproteins, altered macrophage biology, and abnormalities in HDL particles. Acidity enhances lipolytic, proteolytic, and other modifications of LDL and other apoB-containing lipoproteins, and strongly increases their affinity for proteoglycans, and may thus accelerate their retention and the ensuing maladaptive cellular responses within the arterial intima.

79. Sneck M, Nguyen SD, Pihlajamaa T, et al. Conformational changes of apoB-100 in SMase-modified LDL mediate formation of large aggregates at acidic pH. J Lipid Res 2012; 53:1832–1839.
80. Williams KJ, Fisher EA. Wang H, Patterson C. Apolipoprotein-B: the crucial protein of atherogenic lipoproteins. Atherosclerosis: risks, mechanisms, & therapies. Hoboken, NJ, USA: John Wiley & Sons, Inc.; 2015. 291–312.
81. Deevska GM, Sunkara M, Morris AJ, Nikolova-Karakashian MN. Characterization of secretory sphingomyelinase activity, lipoprotein sphingolipid content and LDL aggregation in ldlr−/−mice fed on a high-fat diet. Biosci Rep 2012; 32:479–490.
82. Tabas I, Williams KJ, Borén J. Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications. Circulation 2007; 116:1832–1844.
83. Lao KH, Zeng L, Xu Q. Endothelial and smooth muscle cell transformation in atherosclerosis. Curr Opin Lipidol 2015; 26:449–456.
84. Moore KJ, Sheedy FJ, Fisher EA. Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol 2013; 13:709–721.
85. Williams KJ, Feig JE, Fisher EA. Rapid regression of atherosclerosis: insights from the clinical and experimental literature. Nat Clin Pract Cardiovasc Med 2008; 5:91–102.
86. Bracho-Sanchez E, Ramkhelawon B, Desvignes L, et al. Induction of neural guidance molecule expression in macrophages and dendritic cells by Mycobacterium tuberculosis. J Immunol 2013; 190 (Suppl 1):55.9.
87. Williams KJ. What does HDL do? A new mechanism to slow atherogenesis – but a new problem in type 2 diabetes mellitus. Atherosclerosis 2012; 225:36–38.
88. Hewing B, Moore KJ, Fisher EA. HDL and cardiovascular risk: time to call the plumber? Circ Res 2012; 111:1117–1120.
89. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012; 380:572–580.
90. Bihari-Varga M. Influence of serum high density lipoprotein on the low density lipoprotein-aortic glycosaminoglycan interactions. Artery 1978; 4:504–509.
91. Camejo G, Cortez MM, Lopez F, et al. Factors modulating the interaction of LDL with an arterial lipoprotein complexing proteoglycan: the effect of HDL. Acta Med Scand Suppl 1980; 642:159–164.
92. Umaerus M, Rosengren B, Fagerberg B, et al. HDL2 interferes with LDL association with arterial proteoglycans: a possible athero-protective effect. Atherosclerosis 2012; 225:115–120.
93. Schissel SL, Tweedie-Hardman J, Rapp JH, et al. Rabbit aorta and human atherosclerotic lesions hydrolyze the sphingomyelin of retained low-density lipoprotein. Proposed role for arterial-wall sphingomyelinase in subendothelial retention and aggregation of atherogenic lipoproteins. J Clin Invest 1996; 98:1455–1464.
94. De Nardo D, Labzin LI, Kono H, et al. High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3. Nat Immunol 2014; 15:152–160.
95. Moore KJ, Fisher EA. High-density lipoproteins put out the fire. Cell Metab 2014; 19:175–176.
96. Hewing B, Parathath S, Barrett T, et al. Effects of native and myeloperoxidase-modified apolipoprotein A-I on reverse cholesterol transport and atherosclerosis in mice. Arterioscler Thromb Vasc Biol 2014; 34:779–789.
97. Niyonzima N, Samstad EO, Aune MH, et al. Reconstituted high-density lipoprotein attenuates cholesterol crystal-induced inflammatory responses by reducing complement activation. J Immunol 2015; 195:257–264.
98. Bursill CA, Castro ML, Beattie DT, et al. High-density lipoproteins suppress chemokines and chemokine receptors in vitro and in vivo. Arterioscler Thromb Vasc Biol 2010; 30:1773–1778.
99▪. Nguyen SD, Javanainen M, Rissanen S, et al. Apolipoprotein A-I mimetic peptide 4F blocks sphingomyelinase-induced LDL aggregation. J Lipid Res 2015; 56:1206–1221.

The authors evaluated effects of the apoA-I mimetic peptide 4F on sphingomyelinase (SMase)-modified LDL particles. The results demonstrated that 4F stabilizes LDL particles by preventing SMase-induced conformational changes in apoB-100, thereby blocking SMase-induced LDL aggregation and the resulting increase in LDL retention.

100. Chiba T, Chang MY, Wang S, et al. Serum amyloid A facilitates the binding of high-density lipoprotein from mice injected with lipopolysaccharide to vascular proteoglycans. Arterioscler Thromb Vasc Biol 2011; 31:1326–1332.
101▪. Huang Y, DiDonato JA, Levison BS, et al. An abundant dysfunctional apolipoprotein A1 in human atheroma. Nat Med 2014; 20:193–203.

Evidence that apoA-I modified by a specific enzyme, myeloperoxidase, in human atheromata may be harmful.

102. Nicholls S, Ray K, Ballantyne C, et al. Comparative effects of cholesteryl ester transfer protein inhibition, statin and ezetimide therapy on atherogenic and protective lipid factors: the Accentuate Trial. Innsbruck: 84th European Atherosclerosis Society Congress; 2016.
Keywords:

apolipoprotein-B; atherosclerosis; Mendelian randomization studies; prospective randomized controlled trials; proteoglycan

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.