Hypertension. 2006;47:803-810
Published online before print March 6, 2006,
doi: 10.1161/01.HYP.0000210554.61293.90
(Hypertension. 2006;47:803.)
© 2006 American Heart Association, Inc.
Role of Circulating Karyocytes in the Initiation and Progression of Atherosclerosis
Helena Chon;
Marianne C. Verhaar;
Hein A. Koomans;
Jaap A. Joles;
Branko Braam
From the Departments of Nephrology and Hypertension (H.C., M.C.V., H.A.K., J.A.J., B.B.) and Vascular Medicine (M.C.V.), University Medical Center Utrecht, Utrecht, the Netherlands.
Correspondence to Branko Braam, Department of Nephrology and Hypertension F03.226, University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands. E-mail bbraam{at}gmail.com
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Abstract
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Cardiovascular disease is still hard to predict in an individual.
The main focus in cardiovascular research has been on endothelial
cells and vascular smooth muscle cells of the vessel wall and
their interactions with the blood flow. Alterations in the properties
of the blood have received a lot of attention in biochemical
terms. Interestingly, alterations in the properties of circulating
cells have received less attention. We propose that presence
of 1 or more risk factors together with normal physiological
stimuli induce redox-dependent changes in leukocyte gene transcription
with pathophysiological responses. Thus, risk factors render
leukocytes hypersensitive to normal stimuli. Risk factors can
be subdivided into physical and chemical factors. Superimposed
on physiological regulators of leukocyte function, these risk
factors promote a cellular pro-oxidative state. Redox-sensitive
transcription factors are activated, leading to responses involving
inflammation, adhesion, migration, and additional reactive oxygen
species generation. As a consequence, monitoring of individual
gene expression signatures of these cells could well increase
our understanding of the mechanisms by which leukocytes and,
in particular, monocytes function. Furthermore, transcriptomes
of these cells could be used to investigate the aggressiveness
of the atherosclerotic process or to guide treatment in the
patient with risk factors for atherosclerosis.
Key Words: gene expression • oxidative stress • atherosclerosis • leukocytes
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Introduction
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Despite great advances in our knowledge about initiation and
progression of atherosclerosis, progress with respect to detection
of individuals at risk for cardiovascular events is still limited.
The availability of sophisticated biochemical assays to quickly
and routinely screen soluble factors in large numbers of patients
with atherosclerosis has led to an ever growing number of recognized
cardiovascular risk factors. Nevertheless, methodology to asses
the stage and aggressiveness of atherosclerotic disease is not
available for individual subjects. Therefore, cardiovascular
events are not predictable and, conversely, adequacy of treatment
cannot be measured in an individual. This concern has been expressed
in a call for new definitions and risk assessment strategies
that proposes to classify vulnerable patients by criteria other
than plaque vulnerability.
1
Virchow’s triad (1856) describes changes in blood flow, the vessel wall, and properties of blood as a model for the pathogenesis of thrombosis. This triad may be applicable to the process of atherogenesis. The main focus in cardiovascular research has been on the vessel wall, in particular, endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) and their interactions with the blood flow. Alterations in the properties of the blood have received much attention in biochemical terms. Interestingly, alterations in the properties of circulating cells have received considerably less attention. In a lipid-feeding model, absence of endothelial intercellular adhesion molecule 1, P-selectin, CD18, or combinations of these molecules limited the size of atherosclerotic lesions but did not prevent atherogenesis,2,3 suggesting that activated ECs facilitate rather than initiate leukocyte infiltration and, thus, a more important role for circulating cells in atherogenesis. In this review, we discuss the pivotal role of the third component of the triad, that is, alterations in the properties of the components and the composition of blood, in particular, circulating karyocytes, in the initiation and progression of atherosclerosis. How are the leukocyte subpopulations and progenitor cells involved in the development and progression of atherosclerosis? Are leukocytes pivotal in the initiation of atherosclerosis or just secondary factors in atherogenesis? How is this related to the concept of dysfunctional stem cells?
We propose that circulating karyocytes form the driving force of the disease process. As such, circulating karyocytes can provide valuable information on the disease state of atherosclerosis. Because more and more information is appearing that all cells in the bloodstream with an active transcription apparatus can be relevant for the initiation and progression of atherosclerosis, the karyocyte is central. It also embodies that cells with highly different phases of differentiation are present, from stem cells to specialized lymphocytes. We consider the application of leukocyte gene expression in patients at risk for atherosclerosis for monitoring treatment of risk factors. In our view, correction of aberrant behavior of circulating karyocytes should be considered as a prime target in treatment of the cardiovascular patient.
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Circulating Cells in the Initiation and Progression of Atherosclerosis
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A variety of physicochemical stresses continuously endanger
the integrity of the EC layer. Circulating karyocytes take part
in maintenance and repair on the one hand but are also involved
in lesion formation and progression on the other. We first consider
regular maintenance and repair, with emphasis on progenitor
cells, then the progression of microtrauma of the EC layer to
more advanced lesions and plaque formation, and, finally, plaque
rupture. For the evolution of microtrauma to plaque rupture
we focus on leukocytes, in particular, monocytes and T lymphocytes.
Additionally, the role of circulating karyocytes in EC maintenance
and repair, with emphasis on vascular progenitor cells, is discussed.
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Initiation of Damage to the Vascular Wall
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ECs are constantly experiencing microinjury, which ultimately
can lead to apoptosis and damage. Continuity of the EC layer
is maintained by division of surrounding ECs and by incorporation
of bone marrow–derived EC progenitor cells.
4 Ongoing microinjury,
facilitated by EC dysfunction and impaired endothelial regeneration
and repair, eventually results in lesions evoking an injury
response. Leukocyte adhesion and infiltration, the first histological
sign of atherosclerosis, occurs as a response to injury. The
inflammatory response particularly involves monocytes and T
lymphocytes. Other than the occurrence of endothelial activation
(increased expression of various leukocyte adhesion molecules),
monocytes themselves can respond to physiological changes by
increased adherence to ECs, as was observed in hypertension.
5 Chemotaxis stimulated by monocytes leads to adhesion to ECs
by the secretion of proinflammatory cytokines, such as transforming
growth factor ß and tumor necrosis factor (TNF)
,
thereby inducing M-colony–stimulating factor
6 and adhesion
molecules.
7 T lymphocytes can modulate EC function and, hence,
induce EC dysfunction: T lymphocyte–derived cytokines,
such as TNF-
and IFN-
, inhibit the anticoagulant properties
of EC, induce the expression of adhesion molecules, and stimulate
the formation of gaps between ECs, enhancing leukocyte adhesion
and infiltration.
8 These cytokines also enhance EC antigen presentation
by upregulation of major histocompatibility complex molecules
and enzymes involved in antigen peptide processing and loading,
9 which can be counterbalanced by NO.
10 Thus, EC may induce a
T-cell response and, in turn, activation of T cells may result
in EC dysfunction.
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Foam Cell Formation, Matrix Deposition, and Proliferation in the Vascular Wall
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After the initial contact with the endothelium, monocytes infiltrate
into the subendothelial layer. Once there, macrophage differentiation
with concurrent induction of scavenger receptors facilitates
uptake of oxidized low-density lipoprotein (oxLDL) leading to
the formation of foam cells. The foam cells increase rapidly
in number as they are trapped in the lesion by oxLDL. Even more
oxLDL is formed via reactive oxygen species (ROS) produced by
resident macrophages.
11 T lymphocytes are attracted by inflammatory
cytokines secreted by macrophages, such as inducible protein
10, monokine induced by IFN-
, and IFN-inducible
-chemoattractant.
Consequently, T lymphocytes are activated by oxLDL presented
on major histocompatibility complex molecules in the lesion,
12 which, in turn, causes the additional activation of macrophages,
ECs, and VSMCs. Indeed, T-lymphocyte induction aggravates and
T-cell inhibition attenuates the progression of atherogenesis
in mice.
13,14
During lesion formation, macrophages and T lymphocytes secrete growth factors, such as platelet-derived growth factor15 and VEGF,16 and cytokines, such as IFN-17 and interleukin (IL) 1,15 that stimulate VSMC migration into the intimal layer of the vessel wall. VSMCs, in turn, also secrete growth factors and synthesize extracellular matrix, which forms a fibrous cap, thus becoming an atherosclerotic plaque.15 In addition, monocytes and T lymphocytes secrete CC motif chemokine receptor, which mediates VSMC proliferation.18 To summarize, fibrous lesions grow as blood-derived inflammatory cells, and VSMCs promote the proatherosclerotic actions of each other.
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Circulating Karyocytes and the Fate of Plaques
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In advanced lesions, foam and vascular cells damaged by oxLDL
11 become apoptotic or necrotic and leave a reservoir of extracellular
lipid and cell debris at the core of the lesion.
19 Plaque erosion,
a frequent cause of serious coronary thrombotic events, may
result from local production of inflammatory mediators or by
cytotoxic attack by activated killer T cells, leading to EC
death. Also, activated ECs may degrade the matrix membrane to
which they adhere.
20 Other lesions may develop into vulnerable
plaques. These are characterized by a large lipid reservoir,
filled with many inflammatory cells, and covered with a thin
fibrous cap. Newly formed vessels inside the plaque, stimulated
by angiogenic factors produced by inflammatory cells, are prone
to hemorrhage. Such neovascularization may also cause massive
growth of VSMCs and matrix expansion leading to a much larger
lesion.
20 These vessels may also provide a conduit for entry
of even more inflammatory cells, increasing plaque instability.
21 The fibrous cap is maintained in a delicate way with an important
role of inflammatory cells. Proinflammatory cytokines, such
as IFN-
, are able to inhibit matrix production by VSMCs. Moreover,
inflammatory cells can secrete collagenases, such as matrix
metalloproteinases, that break down matrix. The lesion edge,
rich in foam cells, is, therefore, most prone to rupture. Thus,
the fate of plaques is directed by inflammatory cells.
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Active Participation of Circulating Karyocytes in Atherogenesis
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How could circulating cells become active players in damage?
There are 2 plausible routes that are not mutually exclusive.
A first option is that circulating cells, predominantly monocytes,
become hypersensitive under the influence of physicochemical
stimuli, including classical risk factors for atherosclerosis.
Alternatively, circulating progenitor cells may become dysfunctional
and fail to adequately participate in maintenance and repair
of the vascular wall or even contribute to the formation of
atherosclerotic lesions. Common to various injury pathways is
the imbalance of NO and ROS. It is clear that NO can dampen
many of the proinflammatory responses evoked by monocytes
22 and ECs.
23 Therefore, impaired NO production by ECs seems to
be central in causing atherosclerosis.
24
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The Hypersensitive Leukocyte Hypothesis
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Different types of leukocytes process a wide variety of physiological
stimuli, which act together to establish an adequate immune
response and clearance of dysfunctional cells. We propose that
the presence of 1 or more risk factors together with normal
physiological stimuli induce redox-dependent changes in leukocyte
gene transcription with pathophysiological responses (
Figure 1).
Thus, risk factors render leukocytes hypersensitive to normal
stimuli. This concept translates into differentially affected
function for each circulating cell type. The overall effect
is that all leukocytes become more sensitive and more readily
adhere to and infiltrate into the vessel wall. Risk factors
can be subdivided into physical and chemical factors. Superimposed
on physiological regulators of leukocyte function, these risk
factors promote a cellular pro-oxidative state. Redox-sensitive
transcription factors are activated, leading to responses involving
inflammation, adhesion, migration, and additional ROS generation
(
Figure 1).
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Figure 1. Schematic model of physiological regulators of leukocyte function that evoke pathophysiological responses characteristic of atherosclerosis.
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Physical Factors
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Circulating cells traveling in the bloodstream are subject to
different mechanical forces: hydrostatic pressure, strain through
deformation, and shear stress. Interestingly, limited information
is available about the relationship between leukocyte cell function
and mechanical forces. Intraluminal pressure may have diverse
effects on monocytes and other circulating karyocytes. Hydrostatic
pressure has been shown to increase the proliferatory response
to phytohemagglutin A in monocytes,
25 whereas amiloride-sensitive
sodium channels in human B cells subjected to hydrostatic pressure
are activated via the cytoskeleton.
26 During cyclic strain,
monocytes increase scavenger receptor class A and class B CD36
expression
27 and adhesion via integrins and activation of calmodulin
and inositol triphosphate.
28 Furthermore, mechanical strain
on monocytes induces
c-fos and
c-jun gene expression and activator
protein (AP)-1 activity.
29 Finally, because flow along the central
axis of the vessel is higher than at the perimeter, circulating
karyocytes sense differential flows and, thus, shear stress.
The higher the flow, the greater the flow gradient across the
cell surface, the higher the shear stress imposed on the cell.
Very few studies have assessed the responses of monocytes or
other leukocytes to shear stress. Leukocytes, including monocytes,
display pseudopod (also called lamellipod) retraction in response
to shear stress. Pseudopods are involved in adhesion and migration
of monocytes. Pseudopod retraction is disturbed in endothelial
NO synthase
–/– mice and enhanced by cGMP analogues,
30 which suggests an additional mechanism for increased adhesion
in NO deficiency. Taken together, there is scattered evidence
that monocytes demonstrate a variety of responses to mechanical
forces; however, studies on interactions between the deranged
physical forces in hypertension and enhanced renin–angiotensin
system, ROS, and sympathetic nervous system activity on monocytes
are not available.
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Chemical Factors, in Particular, Angiotensin II, ROS, and Inflammation
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Inappropriate activation of the renin–angiotensin system
is evident in hypertension, uremia, and diabetes.
31 Moreover,
expression of the angiotensin II (Ang II) type 1 (AT
1) receptor
is increased in atherosclerotic lesions.
32,33 Interestingly,
we observed upregulation of the AT
1 receptor in leukocytes of
patients with essential hypertension.
34 Downstream signaling
pathways of the AT
1 receptor can mediate numerous proatherogenic
effects, in particular, enhanced expression of adhesion molecules,
activation of inflammation via nuclear factor
B (NF-
B) activation,
and production of ROS.
31 These proatherogenic effects occur
in ECs and VSMCs and probably also in circulating karyocytes.
Activation of AT
1 receptor–dependent pathways may enhance
adhesion by increased expression of macrophage antigen (Mac)-1
in granulocytes
35 and migration in monocytes.
36 Monocytes are
very sensitive to Ang II stimulation, and Ang II favors differentiation
of monocytes into dendritic cells, implying a role for Ang II
in the invasion of these cells into the vascular wall.
37 Moreover,
cross-linking of AT
1 receptor homodimers in monocytes, which
is activated in hypertensive patients, enhances and prolongs
signaling.
38 In concordance, inhibition of Ang II generation
or AT
1 receptor cross-linking activity reduced the progression
of atherosclerosis in mice.
38 Finally, a recent study indicated
that Ang II strongly induced vascular lesions via enhanced macrophage
infiltration in wild-type mice that received bone marrow from
apolipoprotein E
–/– mice.
39 Circulating karyocytes
that have increased Ang II sensitivity are, thus, transformed
into cells that are more prone to participate in adhesion, lesion
formation, and inflammation, indicating their important role
in atherogenesis.
There is also evidence that a shift in the NO/ROS balance toward oxidative stress can affect circulating karyocytes. Increased ROS production was observed in granulocytes in hypertensive rats35 and patients.40 All of the cell types in the vascular wall,41 as well as circulating karyocytes, such as neutrophils and monocytes, express reduced nicotinamide-adenine dinucleotide phosphate oxidase, a major source of ROS in cardiovascular disease. ROS-induced activation of NF-B, peroxidase proliferator–activated receptor , and other redox-sensitive transcription factors can mediate numerous effects in circulating karyocytes. Moreover, ROS can amplify the actions of IFN- and NF-B activation and enhance adhesion by upregulation of adhesion molecule Mac-1 on neutrophils.42 OxLDL is increased in overt cardiovascular disease and can enhance dendritic cell maturation.43 All in all, ROS and oxidative stress can render leukocytes hypersensitive, favoring the development of atherosclerotic lesions.
Inflammatory regulators, such as cytoplasmic repressor protein, TNF-, IL-1ß, IL-6, and IFN-, are elevated in cardiovascular disease. TNF- and IL-1ß, both strong inflammatory mediators secreted by activated macrophages, are potent inducers of NF-B. Additionally, IL-1ß can stimulate superoxide production directly by activating reduced nicotinamide-adenine dinucleotide phosphate oxidase in neutrophils and macrophages,44 whereas TNF- also activates c-jun. IL-6 has widespread actions in inflammation and mediates these effects via 2 distinct pathways, that is, Janus-activating kinase/signal transducer and activation of transcription and extracellular signal regulated kinase/mitogen- activated protein kinase signaling.45 Finally, the proinflammatory cytokine IFN- is important in the progression of inflammatory responses associated with cardiovascular disease.46–48 Evidence that IFN- promotes atherosclerosis is based on the observation that apolipoprotein E–/–, IFN- receptor double-knockout mice develop less atherosclerosis than apolipoprotein E–/–, IFN- receptor+/+ mice.49,50
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Progenitor Cell Dysfunction and Dysbalance and Atherosclerosis
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Subpopulations of mononuclear stem cells have the capacity not
only to differentiate into hematopoietic cells also to differentiate
into EC and VSMCs, myofibroblasts, cardiomyocytes, pancreatic
cells, and so on, depending on the environment.
12 Vascular progenitor
cells can be isolated and cultured from peripheral blood, and
many studies have demonstrated that endothelial progenitor cells
(EPCs) contribute to neovascularization in response to limb
or myocardial ischemia and to renal microvascular repair. The
capacity of stem cells to develop into differentiated cell types
may alter the course of disease.
As mentioned before, damage to the endothelium is repaired by replication of neighboring ECs and by incorporation of bone marrow–derived EPCs.51 Substantial evidence for a role in repair by EPCs has been derived from experiments applying hindlimb ischemia and studying repair by bone marrow–derived cells.51 Rookmaaker et al52 demonstrated that bone marrow–derived cells could also be found in the endothelial layer of renal vasculature of kidneys with glomerulonephritis. We studied the implications for vascular wall maintenance of the replacement of ECs by EPCs using a mathematical model.53 The competence of EPCs depends on the release from the bone marrow, homing to the site of injury,54 and the actual function, that is, proliferation and secretion of growth factors. Various conditions have been found to alter the release and angiogenesis of EPCs.55–57 It is becoming clear that number, function, and differentiation of progenitor cells can be affected by risk factors for atherosclerosis. For example, a decreased number and impaired function of EPCs have been reported in diabetes58,59 and in uremia,9,60 which may contribute to reduced endothelial regeneration and repair leading to vasculopathy. EPC numbers correlate with combined Framingham score and clinical outcome.61,62 Several reports have also suggested that vascular smooth muscle progenitor cells are present in the circulation, which may contribute to the development of atherosclerosis.54,63,64
Although mechanisms underlying the changes in vascular progenitor cell function are emerging,65 little is known about the influence of chemical factors, such as pressure and shear stress, on EPCs. Chemical factors, such as inflammation, particularly cytoplasmic repressor protein and hyperglycemia, have known detrimental effects on EPC survival and angiogenic capacity.66,67 On the other hand, Ang II stimulates EPC proliferation and EPC-induced angiogenesis,68,69 in contrast to the generally proatherogenic functions of Ang II. Because these experiments were performed with healthy donors, it is conceivable that Ang II signaling is dysregulated in cardiovascular patients. This idea is supported by the finding that angiotensin-converting enzyme inhibitors and AT1 receptor antagonists improve EPC numbers and function in patients with diabetes or coronary artery disease.70,71 In addition, Ang II may accelerate senescence via enhanced oxidative stress.72 Conversely, EPCs, or their pluripotent common precursor, may differentiate into cells with a vascular smooth muscle/myofibroblast phenotype that can have aggravating effects on plaque growth.73 It is, thus, clear that systemic factors also weaken repair mechanisms of the vessel wall.
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Synchronized Hypersensitive Response in the Initiation and Progression of Atherosclerosis
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Apparently, circulating karyocytes are affected by physicochemical
stimuli just as much as EC, because they share the same environment.
Moreover, ECs are known to be important mediators of inflammation
by cytokine secretion and by enhancing leukocyte infiltration.
However, apart from cell characteristics, the response to the
environment could well be different. On the one hand, ECs are
fixed to the vascular wall, with the consequence that neighboring
cells modulate their response. On the other hand, circulating
karyocytes, being exclusively exposed to the circulation, may
be even more sensitive to systemic changes. All in all, atherosclerosis
is most probably to be accompanied by synchronization in the
hypersensitivity displayed by ECs and circulating karyocytes.
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Circulating Karyocytes in Diagnosis and Treatment of (Pro)atherosclerotic Conditions
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Few studies have addressed the possibility of monitoring circulating
karyocytes or monocytes in particular to assess cardiovascular
patients. Individual gene expression signatures of these cells
could well increase our understanding of the mechanisms by which
monocytes function. Furthermore, transcriptomes of these cells
could be used to investigate the aggressiveness of the atherosclerotic
process or to guide treatment in the patient with risk factors
for atherosclerosis.
As mentioned previously, we propose that hypersensitive karyocytes are crucially involved in the development of atherosclerosis. Hypersensitivity or dysfunction of circulating cells may be reflected in aberrant gene expression profiles of these cells. Studying these transcriptomes, for example, using microarrays, may ideally allow determination of the stage of atherosclerotic disease and the tendency for disease progression in an individual. In addition, treatment efficacy may be evaluated in the same fashion. Which information is currently available that supports the feasibility to establish a diagnosis based on gene expression profiles? There are several examples where gene expression profiles offered accurate diagnosis and prognostic data. Studies in the oncology field are particularly successful because of the obvious availability of frozen tissue and the severity of the disease. The best-known examples are in breast cancer74 and lymphomas.75–77 Profiling easily accessible biological material, such as circulating cells, may allow for application of such an approach to many more fields. For lymphomas, this is obviously feasible, but gene expression profiles in other conditions that do not as clearly involve circulating cells have also been studied (Table). Others have also suggested that circulating cells could be useful in cardiovascular disease.78
We recently observed widespread changes in expression of inflammation-related genes in leukocytes from patients with essential hypertension. Microarray data were matched by conventional RT-PCR (Figure 2). This novel finding shows that essential hypertension is a complex systemic disease that involves an inflammatory response, partly by downregulation of anti-inflammatory IL receptors. Leukocytes also displayed differential expression of genes related to blood pressure control,34 in particular, increased expression of AT1 receptor. Strikingly, effective treatment of high blood pressure strongly reduced the number of modulated genes. This finding couples blood pressure to complex transcriptional changes in circulating karyocytes, which seems to be correctable.
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Figure 2. Differential regulation of target genes in patients with essential hypertension (HT) and with treatment (HT+T) as measured by RT-PCR (pools of men and women were processed separately) and by microarray (mean log2-transformed ratios of pools of men and women).
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To reach successful implementation of gene expression profiling of circulating cells for clinical use, several conditions are required. Standardization of blood withdrawal, processing, and storage in all of the participating medical centers is essential for comparability. The microarray technique can be subject to external factors that influence quality; a robust profiling technique is, therefore, needed. A selection of a set of atherosclerosis genes that facilitates use in the clinic would be preferable. Furthermore, microarray data should be presented and made publicly available, for which MIAME provides an excellent format.79 More importantly, microarray data should be interpreted together with clinical parameters. To be able to perform hierarchical clustering and classification strategies that incorporate these clinical data, both continuous and categorical parameters could be scaled to sensible numbers with ranges comparable to those of microarray gene expression ratios. We expect that the powerful combination of expression profiling and the use of circulating karyocytes will set off revolutionary changes in the treatment of cardiovascular patients.
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Conclusions
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In contrast to the general concept of atherosclerosis, circulating
karyocytes are anything but passive bystanders that come into
play only when ECs capture them. Circulating cells are sensitive
to pressure or flow, endothelial dysfunction, and thrombogenic
properties. The study of circulating karyocytes is, therefore,
important in further understanding the mechanism of atherosclerosis.
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Acknowledgments
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B.B. is a research fellow of the Royal Dutch Academy of Arts
and Sciences. Studies mentioned in this report are supported
by grant NS6013 from the Dutch Kidney Foundation. M.C.V. is
supported by the Netherlands Organization for Scientific Research
(NWO grant 016.036.041).
Received November 30, 2005;
first decision December 18, 2005;
accepted February 6, 2006.
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Abstract
Introduction