NDT Advance Access originally published online on April 16, 2007
Nephrology Dialysis Transplantation 2007 22(7):1823-1827; doi:10.1093/ndt/gfm112
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Atherogenesis and inflammation—was Virchow right?
Medizinische Klinik und Poliklinik I, University Medical Center Munich-Grosshadern, Ludwig-Maximilians University of Munich, Munich, Germany
Correspondence and offprint requests to: Michael Weis, MD, Medizinische Klinik I, University Hospital Munich-Grosshadern, 81377 Munich, Germany. Email: Michael.Weis{at}med.uni-muenchen.de
Keywords: atherosclerosis; immune system; innate immunity; adaptive immunity; dendritic cells; toll-like receptors
Atherosclerosis is the most common pathological process leading to cardiovascular disease. The development of endothelial dysfunction, the earliest stage of atherosclerosis, involves genetic and haemodynamic factors as well as other acquired and modifiable risk factors, including smoking, hypercholesterolaemia, diabetes mellitus and hypertension. In addition, it has become clear that innate and adaptive immune systems are involved in the initiation and progression of atherogenesis [1,2].
Already during the 19th century, the pathologists C. von Rokitansky and R. Virchow described cellular inflammatory changes in the atherosclerotic vessel walls [3]. Whereas Virchow supported their primary role, von Rokitansky considered these changes secondary in nature (in response to fibrin-induced alterations) [3].
This article outlines the current knowledge of the role of the immune system in atherogenesis.
 |
Evidence that the immune system is involved in atherosclerosis |
|---|
 Top Evidence that the immune... Innate immune response and...Adaptive immune response in...Antigens implicated in...Uraemia and atherogenic...SummaryReferences |
|---|
Several lines of evidence have been originated to link the immune system to the process of atherogenesis.
First, the presence of immune cells and immune cell products in human and/or experimental atherosclerosis indicates their participation in lesion biology. Atherosclerotic lesion development is mostly confined to regions of arterial curvature and branch points, which are exposed to disturbed blood flow. This has been associated with unique pro-inflammatory gene expression patterns in the vessel wall [4,5].
Atherosclerotic lesions are characterized by the accumulation of lipid particles and cells of the immune system in subendothelial regions, leading to narrowing of the arterial lumen and, following plaque rupture, to thrombosis. Autoimmune elements (e.g. autoantibodies, autoantigens) as well as different inflammatory cells like monocytes, dendritic cells (DCs), macrophages (developing into foam cells), T cells, B cells, natural killer cells (NKCs) and mast cells are involved in these processes [1,2,5,6].
Endothelial dysfunction is not only characterized by biosecretory dysfunction and a loss of anti-thrombogenic properties but also by an immune imbalance with a proinflammatory over an anti-inflammatory phenotype [1,2,7,8]. Hence, endothelial dysfunction results in enhanced adhesion and migration of peripheral circulating monocytes and DCs [9,10]. Retention of mononuclear (antigen-presenting) cells in the vessel wall (due to reduced emigration) is one of the crucial elements of atherogenesis [11,12]. The migration of antigen-presenting cells appears to be limited by platelet-activating factor and lysophosphatidic acid, which are likely to be enriched in progressing lesions [12].
Cytokines are secreted by immune cells within the atherosclerotic plaque. These include interleukin (IL)-1, IL-2, IL-6, IL-8, IL-12, IL-10, tumour-necrosis factor, interferon-
and platelet-derived growth factor [13]. The presence of both proinflammatory and anti-inflammatory cytokines suggests the coexistence of proatherogenic and antiatherogenic influences in lesions [13]. The pattern of cell and cytokine involvement suggests a Th1 dominance in atherosclerotic lesions progression [2,6].
Furthermore, the inflammatory process in the atherosclerotic artery may lead to increased blood levels of inflammatory cytokines and other acute-phase reactants [2]. Activation and differentiation of peripheral circulating immune cells have been linked with clinical disease states of atherosclerosis [14,15].
Second, more compelling evidence for the role of the immune system in atherogenesis derives from specific transgenic and knockout mice. Knockout of mediators of monocyte chemotaxis (e.g. MCP-1, CCR2), IFN- or its receptor, costimulatory molecules, CD40L, toll-like receptors (TLRs) and the RAG genes, resulting in global immunodeficiency, all lead to a reduction in atherosclerosis in mouse models [5,16]. On the other hand, knockout of IL-10, a Th1 inhibitory cytokine, results in an increase in lesions [6].
Third, the direct transfer of immune mediators or vaccination provides a basis for implicating the immune system in atherogenesis. IFN-, IL-12, or IL-18 injection all increase atherosclerosis [5,16]. The administration of antibodies to CD40L reduces lesion formation in LDL receptor-deficient mice, whereas the use of antibodies to TGF-ß in the apoE-deficient mouse increases atherosclerosis, emphasizing the atheroprotective influence of this cytokine [5].
When CD4+ cells from apoE-deficient mice in which the Th1 cell subtype is dominant are transferred to immunodeficient apoE-deficient mice, an increase in atherosclerosis is noted. On the other hand, the transfer of B-cells from apoE-deficient mice with or without T-cells reduces atherosclerosis [5,6]. Vaccination with the heat shock protein (HSP; serving as an autoantigen) increases atherosclerosis [17].
Fourth, atherosclerosis is aggravated in patients with dysregulation of the immune system.
Until recently, disease activity and severity were the most likely causes of death in patients with autoimmune diseases. With the development of better therapies, the long-term sequela of excessive atherosclerosis is becoming increasingly apparent (most studied in SLE, antiphospholipid syndrome and rheumatoid arthritis) [18]. Available data suggest a beneficial net effect of current anti-inflammatory therapies (including steroids) on cardiovascular morbidity and mortality in patients with autoimmune diseases [19,20].
In immunosuppressed patients after heart transplantation, cardiac allograft vasculopathy is the most important cause of death in the long term follow-up. Allograft vasculopathy is characterized by endothelial dysfunction and early vascular inflammation [8].
When further describing the role of the immune system in atherogenesis, it is necessary to differentiate between the impacts of innate vs adaptive immunity (Figure 1).
|
|
Innate immune response and atherosclerosis |
|---|
|
TopEvidence that the immune...Innate immune response and...Adaptive immune response in...Antigens implicated in...Uraemia and atherogenic...SummaryReferences |
|---|
The innate immune system is critical to the initial inflammatory response. The innate immune system consist of epithelial/endothelial barriers and circulating cells and proteins that recognize microbes or substances produced in infections and initiate responses that eliminate the microbes [21] (Figure 1). Crucial pattern recognition and signalling receptors are mannose receptors and scavenger receptors, receptors for opsonins and TLRs [21].
The TLR family, including 12 mammalian TLRs identified to date, recognizes pathogen-associated molecular patterns (PAMPs) on bacterial and viral pathogens. Ligands include lipopolysaccharide (LPS) of Gram-negative bacteria (recognized by TLR4), various bacterial lipids, such as lipoteichoic acid of Gram-positive bacteria, peptidoglycan and lipopeptides (recognized by TLR2 heterodimers with TLR1 or TLR6) [22], as well as viral nucleic acids, double-stranded RNA and DNA rich in CpG-motifs (recognized by intracellular TLR3, TLR7 and TLR 9). In addition to the classical bacterial and viral TLR ligands, several endogenous ligands (HSP; oxidized LDL, oxLDL), produced as a response to stress or tissue injury, have been proposed.
When any one of the several described TLR ligands binds to its TLR, one or several adapter molecules are recruited to propagate the signal via interaction of Toll/IL-1 resistance (TIR) domains present on the TLR and its adapters [22]. Activation of the adapter proteins (like the myeloid differentiation protein-88; MyD88) and its downstream signals results in activation of the NF-
B and interferon pathway.
In particular, TLR1, TLR2 and TLR4 have been found to be expressed in both human and mouse atherosclerotic lesions [23]. Expression has mainly been located to endothelial cells and macrophages within the lesion [24]. Also, patients with acute coronary syndromes or coronary arteriosclerosis disease show increased TLR4 expression on circulating monocytes compared with control patients [15]. The TLR-dependent atherosclerosis contribution may rely on endothelial TLR activation as well as on mononuclear cell TLR activation [15,23,24]. Lack of TLR-4 or lack of the adapter protein MyD-88 reduces atherosclerosis [25,26]. Complete TLR2 deficiency in hyperlipidaemic mice resulted in an approximately 50% reduction in atherosclerotic lesion severity [27].
DCs play a key role in innate and adaptive immunity [28], expressing high levels of scavenger receptors and class II major histocompatibility complexes (MHCs), which present antigens to cells of the adaptive immune system. Dysfunctional endothelium has been shown to drive enhanced DC adhesion, migration and maturation, and activated vascular DCs have been demonstrated in very early stages of atherosclerosis [10,29]. Some DCs cluster with T cells directly within atherosclerotic lesions, while others migrate to lymphoid organs to activate T cells [29]. Dyslipidaemia systemically alters DC function and recent findings suggest that DCs play a role in plaque destabilization [29]. DCs seem to be concentrated in the rupture-prone areas of vulnerable human carotid artery plaques [30,31]. Plasmacytoid DCs in atherosclerotic plaque sense microbial motifs and amplify cytolytic T-cell functions, thus providing a link between host-infectious episodes and acute immune-mediated complications of atherosclerosis [32].
|
Adaptive immune response in atherogenesis |
|---|
|
TopEvidence that the immune...Innate immune response and...Adaptive immune response in...Antigens implicated in...Uraemia and atherogenic...SummaryReferences |
|---|
The adaptive immune system may influence atherosclerosis in several ways (Figure 1): (i) by cell–cell interaction between antigen-presenting cells (like DCs, macrophages, B -cells, NKCs) and T-cells [6]; (ii) by the secretion of a variety of cytokines from activated T-cells, which in turn mediate further activation of plaque-invading inflammatory cells; or (iii) by the production of antibodies by B- cells in a T-cell-dependent or -independent manner. Some of these antibodies have the ability to block the import of modified lipoproteins via macrophage scavenger receptors.
|
Antigens implicated in initiation and progression of atherosclerosis |
|---|
|
TopEvidence that the immune...Innate immune response and...Adaptive immune response in...Antigens implicated in...Uraemia and atherogenic...SummaryReferences |
|---|
Concerning atherogenesis, the adaptive immune system reacts to endogenous neoantigens (e.g. apoptotic cells, HSP and oxidized (ox)-LDL) or exogenous viral and bacterial antigens, resulting in the activation of T -cells and B -cells [6] (Figure 1). Some of these (neo)antigens are also targets of the innate immune system (e.g. pathogen-associated molecular patterns, oxLDL and HSPs ligate-specific TLRs) [24].
oxLDL is the type of LDL cholesterol most likely to be taken up by macrophages that develop into foam cells [33]. Increased levels of anti-oxLDL antibodies have been detected in patients with early-onset peripheral vascular disease, severe carotid atherosclerosis and angiographically verified coronary artery disease (CAD) [33]. In addition, raised levels of oxLDL antibodies were found to be predictive of progression of carotid atherosclerosis, myocardial infarction and death. Elevated levels of these antibodies were found in patients with CAD compared with healthy controls, regardless of the amount of coronary calcification. In animal models, immunization with oxLDL or apolipoprotein B100-epitopes resulted in suppression of early atherosclerosis, suggesting a shifting of the immune response towards an anti-inflammatory TH2 or TH3 response [17]. Additional research is required to characterize the impact of the different antigenic moieties of the LDL molecule.
HSPs are a family of proteins that are highly conserved across different species, from bacteria to humans. Immune responses to microbial HSP 65 can cross-react with human HSP60, which is detected in human atherosclerotic lesions [2]. This process is called molecular mimicry. Patients with atherosclerosis display increased antibody titres to HSP65/60 [15]. Moreover, HSP-60 induces TLR-4 activation in monocytes of patients with an ACS [15], linking processes of innate and adaptive immunity. Immunization with HSP65/60 in mice and rabbits aggravates early atherosclerotic lesion formation, suggesting that adaptive immunity to HSP promotes atherogenesis [34].
Chlamydia, herpes simplex and cytomegalovirus have been detected in atherosclerotic plaques [35], and patients with cardiovascular disease have high antibody titres to Chlamydia pneumoniae, Helicobacter pylori and cytomegalovirus, indicating involvement of adaptive immunity system [35]. The number of infectious pathogens to which an individual has been exposed (pathogen burden) has been linked to the development and the prognosis of CAD [36]. An example how a pathogen might directly induce endothelial function has been shown by human CMV inducing dysregulation of the endothelial nitric oxide pathway [37]. Molecular mimicry between pathogen-associated antigens and human molecules may further contribute to vascular inflammation, leading to the concept that pathogens are conditioning rather than directly infecting the vessel wall [35,38].
|
Uraemia and atherogenic inflammation |
|---|
|
TopEvidence that the immune...Innate immune response and...Adaptive immune response in...Antigens implicated in...Uraemia and atherogenic...SummaryReferences |
|---|
Immune system dysregulation in end-stage renal disease patients is a multifactorial process, combining profound immunodeficiency with a state of cellular immune activation [39].
Renal disease patients are affected by a chronic inflammatory state, represented by higher concentration of CRP, IL-6, and fibrinogen, and lower levels of albumin and negative acute phase molecules as fetuin-A (an independent predictor of cardiovascular mortality) [40–42]. Chronic inflammation is associated with a higher risk of cardiovascular disease in end-stage renal disease.
Although inflammation in renal disease can be caused, at least in part, by reduced renal clearance of TNF-
and IL-6, several pathogenetic mechanisms are likely to contribute to direct activation of the inflammatory process under uraemic conditions [43]. These mechanisms include accumulation of advance glycoxidation end products, production of reactive oxygen species and oxidative damage (mediated by angiotensin II, oxLDL and uraemic toxins), malnutrition, dialysis membrane-induced immune cell activation and chronic infection [43]. Support for direct activation of systemic inflammation provides a strong rationale for use of anti-inflammatory treatments in uraemia.
Large, prospective and controlled endpoint studies for cardiovascular disease in renal disease patients are not yet available. Therefore, based on the increased cardiovascular risk in renal patients, nephrologists have to extrapolate from non-renal population-based studies. The vasculoprotective and anti-inflammatory effects of aspirin, inhibitors of the renin–angiotensin aldosterone system and statins have been well described. In contrast, the antioxidants vitamin E and C, and ß-carotene have failed to demonstrate a positive effect on cardiovascular mortality. Intriguingly, the phosphate binder sevelamer and the antioxidant N-acetylcysteine are capable of preventing uraemia-enhanced atherosclerosis progression in apoE–/– mice [44,45].
|
Summary |
|---|
|
TopEvidence that the immune...Innate immune response and...Adaptive immune response in...Antigens implicated in...Uraemia and atherogenic...SummaryReferences |
|---|
The systemic immune system as well as the local vascular immune system is involved in the development and progression of atherosclerosis. As a consequence of constitutive trafficking, different leukocyte populations already reside in normal aorta before the onset of atherosclerosis. The development and progression of atherosclerosis is mainly determined by endothelial dysfunction with subsequent adhesion, activation and differentiation of leukocytes as well as by the interaction between antigen-presenting cells and T cells. Pathogens, PAMPs and auto-antigens are contributing to vascular inflammation via activation of the innate and adaptive immune system. Virchow was right when assigning inflammation a primary role in the atherosclerotic disease process.
Conflict of interest statement. None declared.
|
References |
|---|
|
TopEvidence that the immune...Innate immune response and...Adaptive immune response in...Antigens implicated in...Uraemia and atherogenic...SummaryReferences |
|---|
- Ross R. Atherosclerosis – an inflammatory disease. N Engl J Med (1999) 340:115–126.
[Free Full Text] - Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med (2005) 352:1685–1695.
[Free Full Text] - Mayerl C, Lukasser M, Sedivy R, Niederegger H, Seiler R, Wick G. Atherosclerosis research from past to present–on the track of two pathologists with opposing views, Carl von Rokitansky and Rudolf Virchow. Virchows Arch (2006) 449:96–103.[CrossRef][ISI][Medline]
- Jongstra-Bilen J, Haidari M, Zhu SN, Chen M, Guha D, Cybulsky MI. Low-grade chronic inflammation in regions of the normal mouse arterial intima predisposed to atherosclerosis. J Exp Med (2006) 203:2073–2083.
[Abstract/Free Full Text] - Getz GS. Thematic review series: the immune system and atherogenesis. Immune function in atherogenesis. J Lipid Res (2005) 46:1–10.
[Abstract/Free Full Text] - Robertson AK, Hansson GK. T cells in atherogenesis: for better or for worse? Arterioscler Thromb Vasc Biol (2006) 26:2421–2432.
[Abstract/Free Full Text] - Methe H, Edelman ER. Cell-matrix contact prevents recognition and damage of endothelial cells in states of heightened immunity. Circulation (2006) 114([1 Suppl]):I233–I238.[ISI][Medline]
- Weis M, von Scheidt W. Coronary artery disease in the transplanted heart. Annu Rev Med (2000) 51:81–100.[CrossRef][ISI][Medline]
- Quehenberger O. Thematic review series: the immune system and atherogenesis. Molecular mechanisms regulating monocyte recruitment in atherosclerosis. J Lipid Res (2005) 46:1582–1590.
[Abstract/Free Full Text] - Weis M, Schlichting CL, Engleman EG, Cooke JP. Endothelial determinants of dendritic cell adhesion and migration. New implications for vascular diseases. Arterioscler Thromb Vasc Biol (2002) 22:1817–1823.
[Abstract/Free Full Text] - Ludewig B, Laman JD. The in and out of monocytes in atherosclerotic plaques: balancing inflammation through migration. Proc Natl Acad Sci USA (2004) 101:11529–11530.
[Free Full Text] - Llodra J, Angeli V, Liu J, Trogan E, Fisher EA, Randolph GJ. Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques. Proc Natl Acad Sci USA (2004) 101:11779–11784.
[Abstract/Free Full Text] - Kofler S, Nickel T, Weis M. Role of cytokines in cardiovascular diseases: a focus on endothelial responses to inflammation. Clin Sci (2005) 108:205–213.[CrossRef][ISI][Medline]
- Methe H, Brunner S, Wiegand D, Nabauer M, Koglin J, Edelman ER. Enhanced T-helper-1 lymphocyte activation patterns in acute coronary syndromes. J Am Coll Cardiol (2005) 45:1939–1945.
[Abstract/Free Full Text] - Methe H, Kim JO, Kofler S, Weis M, Nabauer M, Koglin J. Expansion of circulating Toll-like receptor 4-positive monocytes in patients with acute coronary syndrome. Circulation (2005) 111:2654–2661.
[Abstract/Free Full Text] - Binder CJ, Chang MK, Shaw PX, et al. Innate and acquired immunity in atherogenesis. Nat Med (2002) 8:1218–1226.[CrossRef][ISI][Medline]
- Shah PK, Chyu KY, Fredrikson GN, Nilsson J. Immunomodulation of atherosclerosis with a vaccine. Nat Clin Pract Cardiovasc Med (2005) 2:639–646.[CrossRef][ISI][Medline]
- Sherer Y, Shoenfeld Y. Mechanisms of disease: atherosclerosis in autoimmune diseases. Nat Clin Pract (2006) 2:99–106.[CrossRef]
- Giles JT, Post W, Blumenthal RS, Bathon JM. Therapy Insight: managing cardiovascular risk in patients with rheumatoid arthritis. Nat Clin Pract (2006) 2:320–329.[CrossRef]
- Roman MJ, Shanker BA, Davis A, et al. Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus. N Engl J Med (2003) 349:2399–2406.
[Abstract/Free Full Text] - Karin M, Lawrence T, Nizet V. Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell (2006) 124:823–835.[CrossRef][ISI][Medline]
- Kawai T, Akira S. Pathogen recognition with toll-like receptors. Curr Opin Immunol (2005) 17:338–344.[CrossRef][ISI][Medline]
- Michelsen KS, Arditi M. Toll-like receptor signaling and atherosclerosis. Curr Opin Hematol (2006) 13:163–168.[Medline]
- Bjorkbacka H. Multiple roles of toll-like receptor signaling in atherosclerosis. Curr Opin Lipidol (2006) 17:527–533.[ISI][Medline]
- Bjorkbacka H, Kunjathoor VV, Moore KJ, et al. Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nat Med (2004) 10:416–421.[CrossRef][ISI][Medline]
- Michelsen KS, Wong MH, Shah PK, et al. Lack of toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc Natl Acad Sci USA (2004) 101:10679–10684.
[Abstract/Free Full Text] - Mullick AE, Tobias PS, Curtiss LK. Modulation of atherosclerosis in mice by toll-like receptor 2. J Clin Invest (2005) 115:3149–3156.[CrossRef][ISI][Medline]
- Nestle FO, Banchereau J, Hart D. Dendritic cells: on the move from bench to bedside. Nat Med (2001) 7:761–765.[CrossRef][ISI][Medline]
- Bobryshev YV. Dendritic cells in atherosclerosis: current status of the problem and clinical relevance. Eur Heart J (2005) 26:1700–1704.
[Abstract/Free Full Text] - Millonig G, Niederegger H, Rabl W, et al. Network of vascular-associated dendritic cells in intima of healthy young individuals. Arterioscler Thromb Vasc Biol (2001) 21:503–508.
[Abstract/Free Full Text] - Yilmaz A, Weber J, Cicha I, et al. Decrease in circulating myeloid dendritic cell precursors in coronary artery disease. J Am Coll Cardiol (2006) 48:70–80.
[Abstract/Free Full Text] - Niessner A, Sato K, Chaikof EL, Colmegna I, Goronzy JJ, Weyand CM. Pathogen-sensing plasmacytoid dendritic cells stimulate cytotoxic T-cell function in the atherosclerotic plaque through interferon-{alpha}. Circulation (2006) 114:2482–2489.
[Abstract/Free Full Text] - Kearney JF. Immune recognition of OxLDL in atherosclerosis. J Clin Invest (2000) 105:1683–1685.[ISI][Medline]
- Lamb DJ, El-Sankary W, Ferns GA. Molecular mimicry in atherosclerosis: a role for heat shock proteins in immunisation. Atherosclerosis (2003) 167:177–185.[CrossRef][ISI][Medline]
- Ludewig B, Krebs P, Scandella E. Immunopathogenesis of atherosclerosis. J Leukocyte Biol (2004) 76:300–306.
[Abstract/Free Full Text] - Smieja M, Gnarpe J, Lonn E, et al. Multiple infections and subsequent cardiovascular events in the Heart Outcomes Prevention Evaluation (HOPE) Study. Circulation (2003) 107:251–257.
[Abstract/Free Full Text] - Petrakopoulou P, Kubrich M, Pehlivanli S, et al. Cytomegalovirus infection in heart transplant recipients is associated with impaired endothelial function. Circulation (2004) 110([11 Suppl 1]):II207–II212.[ISI][Medline]
- Stassen FR, Vega-Cordova X, Vliegen I, Bruggeman CA. Immune activation following cytomegalovirus infection: more important than direct viral effects in cardiovascular disease? J Clin Virol (2006) 35:349–353.[CrossRef][ISI][Medline]
- Descamps-Latscha B, Jungers P, Witko-Sarsat V. Immune system dysregulation in uremia: role of oxidative stress. Blood purificat (2002) 20:481–484.[CrossRef]
- Honda H, Qureshi AR, Heimburger O, et al. Serum albumin, C-reactive protein, interleukin 6, and fetuin a as predictors of malnutrition, cardiovascular disease, and mortality in patients with ESRD. Am J Kidney Dis (2006) 47:139–148.[CrossRef][ISI][Medline]
- Zoccali C, Tripepi G, Mallamaci F. Predictors of cardiovascular death in ESRD. Semin Nephrol (2005) 25:358–362.[CrossRef][ISI][Medline]
- Ketteler M, Bongartz P, Westenfeld R, et al. Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet. (2003) 361:827–833.[CrossRef][ISI][Medline]
- Galle J, Seibold S, Wanner C. Inflammation in uremic patients: what is the link? Kidney Blood Press R (2003) 26:65–75.[CrossRef]
- Phan O, Ivanovski O, Nguyen-Khoa T, et al. Sevelamer prevents uremia-enhanced atherosclerosis progression in apolipoprotein E-deficient mice. Circulation (2005) 112:2875–2882.
[Abstract/Free Full Text] - Ivanovski O, Szumilak D, Nguyen-Khoa T, et al. The antioxidant N-acetylcysteine prevents accelerated atherosclerosis in uremic apolipoprotein E knockout mice. Kidney Int (2005) 67:2288–2294.[CrossRef][ISI][Medline]
Accepted in revised form: 8. 2.07
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||