Leukocytes and complement in atherosclerosis
Alipour, A.
Citation
Alipour, A. (2012, February 9). Leukocytes and complement in atherosclerosis. Retrieved from https://hdl.handle.net/1887/18459
Version: Corrected Publisher’s Version
License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden
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published in part in
Atherosclerosis suppl 2008;9:39–44
Gene ral introduction and
outline of the thesis
INTRODUCTION
Atherosclerosis is one of the major causes of death in the world. Cardiovascular mortality accounts for 30% of all deaths in the Netherlands (1). Previous studies have undoubtedly shown that infl ammation is closely linked to atherosclerosis (2-6). Infl ammatory markers such as C-reactive protein (CRP), leukocyte count and complement component 3 (C3) have been linked to cardiovascular disease (CVD) as well as to hyperlipidemia, insulin resistance and dia- betes mellitus (3,7-17). Elevation of these parameters may cause activation of endothelial cells and leukocytes. It has been shown that lipoproteins, triglycerides (TG), fatty acids and glucose can activate endothelial cells in part due to the production of reactive oxygen species (18-27).
So lipids and glucose, together with other classical risk factors, form the start of the cascade eventually leading to plaque formation and atherosclerosis (Figure 1).
Lipids, glucose, sedentary lifestyle, smoking, hypertension, inflammatory disease and genetics
Inflammation: leukocytes, platelets, CRP and complement Endothelial dysfunction
Plaque rupture and vascular events
Plaque formation Cytokines
ROS
The general outline of the steps in atherogenesis from risk factors to vascular events: Risk factors such as lipids, glucose, sedentary lifestyle, smoking, hypertension, infl ammatory disease and genetics contribute to leukocyte, CRP and complement activation. Concomitant activation of endothelial cells by the risk factors also occurs. Then, the activated endothelial cells express cytokines functioning as chemotactic factors for monocytes and T-cells. These chemotactic factors play a role throughout the process. The leukocytes can also activate the endothelium and induce the expression of cellular adhesion molecules (CAMs) and selectins, facilitating adherence of all leukocytes. Platelet activation and binding is also necessary. This will lead to adherence of these cells to the endothelium as well as the production of chemoattractants leading to the recruitment and activation of other leukocytes. The activated leukocytes are able to produce reactive oxygen species (ROS), which destabilize atherosclerotic lesions. Leukocytes transmigrate across the endothelial wall. Monocytes residing in the arterial wall diff erentiate into macrophages. Oxidative modifi cation of LDL and remnants results in a highly atherogenic particle that can easily be taken up by macrophages. The latter can activate endothelial cells resulting in production of CAMs and pro-infl ammatory cytokines (IL-6, IL-8 and MCP-1). Defects in the C3/ASP system (Alternative Pathway) leads to an enhanced fl ux of hepatic free fatty acids to the liver, which will in turn up-regulate hepatic VLDL secretion. The increase of lipoproteins in the bloodstream activates the Classical Pathway by CRP and binding of C3 to these lipoproteins (HDL
3). Within the sub-endothelium the macophages and foam cells also activate the Classical Pathway of the complement system. The activation of this pathway will promote leukocyte activation.
Plaque formation proceeds due to persistent risk factors, endothelial dysfunction and infl ammation,
eventually leading to plaque rupture and vascular events.
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Although infl ammation is indeed an important feature of atherogenesis, and many factors have been identifi ed to play an important role in the infl ammatory cascade, the exact trig- gers and the molecular basis have not been elucidated. Many investigators have studied the consequences of the infl ammatory reaction, for example CRP has been proposed to play a role in the initiation and the propagation of atherosclerosis, and acute changes like plaque rupture (3-6). In these processes, leukocytes and complement seem to play a crucial role.
In the following sections, we will introduce the role of TG, TG-rich lipoproteins, hyperglycemia, leukocytes and mannose binding lectin (one of the activators of complement) in atherosclerosis.
TRIGLYCERIDE-RICH LIPOPROTEINS AND POSTPRANDIAL HYPERLIPIDEMIA
Disturbances of TG metabolism are closely associated to atherosclerosis (28). There is a close correlation between fasting and postprandial TG, although inter-individual diff erences may be high, in part due to diff erences in insulin sensitivity (29,30). Subjects with fasting hypertriglyc- eridemia usually have elevated postprandial lipemia. Patients with obesity, diabetes mellitus and the metabolic syndrome have also postprandial hyperlipidemia (31). One of the proposed mechanisms has been competition between endogenous and exogenous TG-rich lipoproteins (TRLs) at diff erent TG catabolic sites by overproduction of very low density lipoproteins (VLDL) in the liver, in part due to hepatic insulin resistance. However, also patients with atherosclerosis with and without the metabolic syndrome, even in the presence of normal fasting TG, have postprandial hyperlipidemia (32,33). Consequently, postprandial hyperlipidemia is a general- ized phenomenon in high-risk conditions for atherosclerosis.
In the event that the liver is overproducing VLDL particles, like in (central) obesity, the metabolic syndrome, type 2 diabetes and familial combined hyperlipidemia (FCH) (31,34,35), the com- mon catabolic steps for VLDL and chylomicrons become saturated resulting in accumulation of both VLDL and chylomicron remnants. According to the classical concept of atherosclerosis by postprandial lipemia, remnant lipoproteins penetrate the vessel wall and are taken up by monocytes inducing foam cell formation. This may be one of the fi rst steps in atherogenesis.
Recent studies suggest alternative mechanisms. Postprandial TRLs of hyperlipidemic patients,
and not of normotriglyceridemic subjects, modulate pro-infl ammatory genes in endothelial
cells and prolong the reduction of fl ow-mediated dilatation beyond 8 hours postprandially
(36). Postprandial and remnant lipoproteins may induce the expression of leukocyte adhesion
molecules on the endothelium, facilitating recruitment of infl ammatory cells. Activation of only
endothelial cells is not suffi cient to initiate the process of atherogenesis. Leukocyte activation
and binding to the endothelium are obligatory steps (2). A cytokine-controlled sequential
up-regulation of selectins and adhesion molecules on activated leukocytes and endothelial
cells is necessary. It has been shown that neutrophils increase postprandially with concomi-
tant production of pro-infl ammatory cytokines and oxidative stress and that these changes
may contribute to endothelial dysfunction (36-38). In healthy volunteers and in patients with premature atherosclerosis postprandial lipemia has been associated with the up-regulation of leukocyte activation markers (38). Fasting leukocytes of patients with CVD have an increased lipid content when compared to controls and it was suggested that this was due to the uptake of chylomicrons in the circulation (39). Increased residence time of atherogenic lipoproteins in plasma will result in enhanced binding of these particles to the endothelium thereby creating a marginated pool of endothelial bound lipoproteins (40), increasing the level of activation of the endothelial cells which potentially will expose more adhesion molecules on their surface (41).
These series of events will ultimately lead to the adhesion of infl ammatory cells (especially, monocytes and lymphocytes but potentially also neutrophils) to the activated endothelium.
Therefore, we have hypothesized that atherogenesis may start in the blood stream and not in the sub-endothelium as generally considered.
HYPERGLYCEMIA
In line with hypertriglyceridemia, hyperglycemia has also been associated to atherosclerosis.
Strong epidemiological evidence supports an association between glycemic control and CVD risk (42,43). It has been proposed that postprandial hyperglycemia may be a stronger risk fac- tor for CVD than fasting glycemia (44,45). Glucose exposure leads to the expression of several infl ammatory genes, including adhesion molecules that facilitate monocyte adhesion to endothelial cells (46). Monocytes grown in high glucose conditions show evidence of increased expression of the cytokines, interleukin-1β and interleukin-6 (47). Scavenger receptors on arte- rial macrophages can take up modifi ed lipoproteins, including low density lipoproteins (LDL) that have become oxidized as a result of glucose-mediated oxidative stress (48). Auto-oxidation of glucose leads to the formation of several reactive oxygen species such as the superoxide anion, and can facilitate LDL oxidation in vitro (48). Alterations in the delivery and removal of lipids from macrophages by lipoproteins and other proteins that have been modifi ed by prolonged exposure to high glucose conditions might lead to lipid accumulation and foam cell formation.
Acute stimulatory eff ects of glucose infusion on leukocyte rolling and adherence to the endo- thelium have been demonstrated in the rat. This eff ect is likely due to elevated glucose per se, and could be normalized by insulin treatment (49). Overexpression of glucose transporter-1 in arterial smooth muscle cells demonstrated that increased glucose metabolism in these cells leads to reduced apoptosis following vascular injury (50). Thus, glucose appears to directly and acutely stimulate leukocyte adherence to the vascular wall and smooth muscle accumulation.
Infl ammatory mechanisms have been associated with postprandial hyperlipidemia and
hyperglycemia. These mechanisms include postprandial leukocyte activation, postprandial
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up-regulation of infl ammation-associated genes in the endothelial cells and the activation of the complement system (13,17,18,36,37,38,51).
LEUKOCYTE ACTIVATION
As mentioned above, both postprandial hyperlipidemia and hyperglycemia induce leukocyte activation. Still, our knowledge concerning leukocyte activation and the relation to atherogen- esis in vivo is limited and is mostly derived from in vitro studies. However, previous studies, also from our group, have shown that triglycerides and fatty acids play an important role as they increase the neutrophil count and activation markers such as CD11b on neutrophils (37,52) and monocytes (52,53) as well as an increase of neutrophil degranulation marker CD66b (52).
Regional diff erences in leukocyte activation was found during coronary angiography in subjects with unstable angina compared to patients with stable angina and healthy subjects, based on a lower intracellular content of myeloperoxidase in leukocytes in the coronary bed compared to peripheral samples (54). By measuring the expression of neutrophil and monocyte CD11b/
CD18 adhesion molecules Mazzone et al. and de Servi et al. (55,56), observed an upregulation of leukocyte adhesion marker CD11b/CD18 in the coronary sinus when compared to the aorta and the ‘postobstructive chamber’, in patients with unstable angina. There were no signifi cant diff erences in patients with stable angina. These data are in some way unexpected because atherosclerosis is considered to be a generalized process and not a localized phenomenon (2). Indeed, van Oostrom et al. observed an increase in CD11b expression (a marker for fi rm adhesion of leukocytes to the endothelium) on neutrophils and monocytes, and CD66b (a degranulation marker) on neutrophils in peripheral blood of diabetic patients compared to healthy subjects (57). All these data show that leukocytes have a central role in atherosclerosis (Figure 1).
COMPLEMENT AND MANNOSE BINDING LECTIN
In the past few years several pro-infl ammatory genes have been identifi ed, which have been suggested to play a role in atherosclerosis. One of these genes is the mannose binding lectin (MBL) gene. MBL defi ciency has been associated to coronary artery disease (CAD), increased intima-media thickness in carotid arteries (58-60) and atherosclerosis in diff erent clinical situ- ations (61-63).
MBL is an important activating factor of the lectin pathway of the complement system (64). The
MBL2 gene codes for the active MBL protein and has three known mutations: allele B at codon
54 (G54D, rs1800450), allele C at codon 57 (G57E, rs1800450) and allele D at codon 52 (R52C,
rs5030737) (65,66). These mutations lead to structural abnormalities and cause MBL defi ciency
(65). The wild-type codon is allele A. Moreover, there are two mutations in the promoter region at –550 (H/L, rs11003125) and –221 (Y/X, rs7096206), which result in a decreased synthesis of the protein (66-68). The alleles interact with each other to form MBL2 ‘secretor haplotypes’
producing high, intermediate and low MBL levels (66,67).
The role of MBL in atherosclerosis is unsettled since several recent studies have suggested that not only low, but also high MBL levels are associated with atherosclerosis (69-73).
OUTLINE OF THIS THESIS
This thesis consists of three parts. Part I describes the eff ects of triglyceride-rich lipoproteins and
glucose on leukocyte activation, and evaluates whether apolipoprotein B48 is associated with
intima-media thickness, a surrogate marker of atherosclerosis. Part II focuses on the degree of
leukocyte activation in coronary artery disease, as well as gender diff erences in leukocyte acti-
vation. Part III investigates the role of mannose binding lecting in postprandial hyperlipidemia
and atherosclerosis, and describes a novel anti-atherogenic concept.
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