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Gerard Pasterkamp

Publications and source records attributed to Gerard Pasterkamp.

At least 37 records · Page 2Linked to original sources
PubMed2004

Athero-express: differential atherosclerotic plaque expression of mRNA and protein in relation to cardiovascular events and patient characteristics. Rationale and design.

In clinical practice, biological markers are not available to routinely assess the progression of atherosclerotic disease or the development of restenosis following endarterectomy or catheter based interventions. Endarterectomy procedures provide an opportunity to study mechanisms of restenosis and progression of atherosclerotic disease since atherosclerotic tissue is obtained. Athero-Express is an ongoing prospective study, initiated in 2002, with the objective to investigate the etiological value of plaque characteristics for long term outcome. Patients are included who undergo an endarterectomy of the carotid artery. At baseline blood is withdrawn, patients fill in an extensive questionnaire and diagnostic examinations are performed. Atherosclerotic plaques are freshly harvested, immunohistochemically stained and examined for the presence of macrophages, smooth muscle cells, collagen and fat. Parts of the atherosclerotic plaques are freshly frozen to study protease activity and protein and RNA expressions. Patients undergo a duplex follow up to assess procedural restenosis (primary endpoint) at 3 months, 1 year and 2 years. Secondary endpoints encompass major adverse cardiovascular events. In the future, the creation of this biobank with atherosclerotic specimen will allow the design of cross-sectional and follow up studies with the objective to investigate the expression of newly discovered genes and proteins and their interaction with patients and plaque characteristics in the progression of atherosclerotic disease. Objective is to include 1000-1200 patients in 5 years. In January 2004, 289 patients had been included. It is expected that 250 patients will be included yearly.

Arteriosclerosis↗
PubMed2004

IgM antibody level against proinflammatory bacterial peptidoglycan is inversely correlated with extent of atherosclerotic disease.

OBJECTIVE: Atherosclerosis may lead to acute clinical events by rupture of a vulnerable atherosclerotic plaque. Previously, we demonstrated that peptidoglycan (PGN), a major cell wall component of gram-positive bacteria that induces production of proinflammatory cytokines through TLR2 and CD14, is prevalent in atherosclerotic lesions with histological features associated with plaque vulnerability. We hypothesized that in atherosclerotic patients antibody levels against PGN may differ compared with matched controls. METHODS AND RESULTS: ELISA was performed to measure immunoglobulin levels against PGN in sera of 80 atherosclerotic patients versus 77 control patients with an increased cardiovascular risk, frequency-matched for age, sex and risk factors for atherosclerotic disease. In all patients and controls, intima-media (IMT) thickness was assessed using an array transducer. Significantly lower levels of IgM directed against PGN were found in atherosclerotic patients compared with the control patients without clinically manifested disease (P = 0.02). The IgM levels against PGN decreased with increasing mean common carotid IMT thickness (P = 0.006). CONCLUSIONS: These results show that patients suffering from atherosclerotic disease have decreased IgM levels against PGN. The data suggest that an antibody response against PGN could have a protective effect against the development or activity of atherosclerotic disease.

Adult↗
PubMed2004

Matrix metalloproteinase inhibition reduces intimal hyperplasia in a porcine arteriovenous-graft model.

BACKGROUND: The patency of arteriovenous (AV) polytetrafluoroethylene grafts for hemodialysis is impaired by intimal hyperplasia (IH) at the venous outflow tract. IH mainly consists of vascular smooth muscle cells, fibroblasts, and extracellular matrix proteins. Because matrix metalloproteinases (MMPs) are enzymes able to degrade extracellular matrix proteins such as elastin and collagen and also stimulate migration of vascular smooth muscle cells, we hypothesized that BB2983 (a broad-spectrum MMP inhibitor) could reduce IH in AV grafts. METHODS: In 12 pigs, AV grafts were created bilaterally between the carotid artery and the jugular vein. Six pigs received the oral MMP inhibitor (MMPi), and six pigs served as a control. Four weeks after AV shunting, the grafts and adjacent vessels were excised and underwent histologic analysis. Quantification of elastin content was performed on Elastin von Gieson-stained sections. RESULTS: At the venous outflow tract, IH was strongly inhibited after MMPi when compared with the control group (1.02 +/- 0.26 mm(2) vs 2.14 +/- 0.38 mm(2); P =.027). The medial area did not differ significantly. In the control group elastin density decreased compared with nonoperated veins. This decrease was not observed in the MMPi group (nonoperated, 6.3% +/- 0.4%; MMPi, 7.2% +/- 0.7% vs untreated, 3.6% +/- 0.5%; P =.0004). Outward remodeling of the vein was not influenced by MMP inhibition. CONCLUSION: MMPi reduces IH formation at the venous outflow tract of AV grafts in pigs, probably by inhibiting elastin degradation. These data suggest that MMP inhibitors might be useful for minimizing IH in AV grafts, thus prolonging patency rates of AV grafts in patients on hemodialysis.

Animals↗
PubMed2004

Functional role for toll-like receptors in atherosclerosis and arterial remodeling.

PURPOSE OF REVIEW: Activation of inflammatory cascades is causally related to the development of atherosclerotic disease. Toll-like receptors are innate immune receptors that recognize pathogen-associated molecular patterns. In this review the pathways by which toll-like receptors might play a role in the development and progression of atherosclerosis will be discussed according to recent literature. RECENT FINDINGS: Toll-like receptors are expressed in atherosclerotic tissue. Next to pathogens, endogenous toll-like receptor ligands have been linked with the development of arterial occlusive disease. In mouse models of hyperlipidemia, a potential role for the toll-like receptor pathway has been suggested in hypercholesterolemia-induced atherosclerosis. Recent in-vitro studies revealed a mechanism by which toll-like receptor ligation results in a strong inhibition of cholesterol efflux from macrophages. In addition, oxidized lipoproteins interact with toll-like receptors. Furthermore, activation of the apoptotic cascade, which is important during atherogenesis, enhances the toll-like receptor pathway resulting in upregulation of proinflammatory cytokines. Human epidemiologic studies have linked TLR4 polymorphism with atherosclerosis. However, data on the association between atherosclerosis progression and TLR4 polymorphisms are conflicting. Next to plaque growth, arterial remodeling is an important determinant of luminal narrowing in atherosclerosis. Recently, a possible role for TLR4 signaling in arterial remodeling has been revealed in mouse models. SUMMARY: A clarification of the molecule [corrected] mechanisms by which the toll-like receptor signaling cascade influences atherosclerosis might [corrected] lead to novel strategies to intervene in the development of this life-threatening disease.

Animals↗
PubMed2004

Local overexpression of C-type natriuretic peptide ameliorates vascular adaptation of porcine hemodialysis grafts.

BACKGROUND: Outflow obstruction at the outflow tract of arteriovenous grafts contributes significantly to the poor patency rates of dialysis grafts in vivo. We addressed the potential of local periadventitial gene therapy at the outflow tract for improving access patency in a validated porcine model of arteriovenous grafts using an adenoviral vector encoding murine C-type natriuretic peptide (Ad.CNP). METHODS: Gene transfer efficiency and optimal virus concentration were determined using Ad.LacZ on porcine jugular veins in vivo (N= 2). Next, in 14 pigs, arteriovenous grafts were implanted bilaterally between the carotid artery and the jugular vein, followed local venous transduction with Ad.CNP (right) and Ad.mock (left). Transduction efficiency of Ad.CNP was evaluated by reverse transcription-polymerase chain reaction (RT-PCR) and cyclic guanosine monophosphate (cGMP) measurements (N= 2). Fourteen days after gene transfer, arteriovenous grafts were excised for histologic analysis (N= 12). RESULTS: Ad.LacZ transduction (1 x 10E10 IU) of porcine veins resulted in evident expression of beta-galactosidase, mainly in the adventitia. At termination, intima/media ratio was decreased by 37% in CNP-treated veins, predominantly due to medial thickening (Ad.CNP 3.1 +/- 0.6 mm(2) vs. Ad.mock 1.70 +/- 0.3 mm(2); P < 0.01) rather than decreased intimal hyperplasia (NS). Adventitial delivery of CNP resulted in increased external elastic lamina (EEL) (Ad.CNP 11.8 +/- 1.4 mm vs. Ad.mock 9.4 +/- 1.0 mm; P= 0.04) and luminal area (Ad.CNP 10.7 +/- 1.4 mm(2) vs. Ad.mock 8.8 +/- 1.7 mm(2); P= 0.05) at the venous anastomosis. CONCLUSION: Overexpression of CNP enhances venous medial thickening and increases outward remodeling in the outflow tract of porcine arteriovenous grafts. These findings underscore the potential of local gene-therapeutic interventions in preventing luminal narrowing at the outflow tract of hemodialysis grafts.

Adenoviridae↗
PubMed2003

Toll-like receptor 4 is involved in outward arterial remodeling.

BACKGROUND: Toll-like receptor 4 (Tlr4) is the receptor for exogenous lipopolysaccharides (LPS). Expression of endogenous Tlr4 ligands, heat shock protein 60 (Hsp60) and extra domain A of fibronectin, has been observed in arthritic and oncological specimens in which matrix turnover is an important feature. In atherosclerosis, outward remodeling is characterized by matrix turnover and a structural change in arterial circumference and is associated with a vulnerable plaque phenotype. Since Tlr4 ligands are expressed during matrix turnover, we hypothesized that Tlr4 is involved in arterial remodeling. METHODS AND RESULTS: In a femoral artery cuff model in the atherosclerotic ApoE3 (Leiden) transgenic mouse, Tlr4 activation by LPS stimulated plaque formation and subsequent outward arterial remodeling. With the use of the same model in wild-type mice, neointima formation and outward remodeling occurred. In Tlr4-deficient mice, however, no outward arterial remodeling was observed independent of neointima formation. Carotid artery ligation in wild-type mice resulted in outward remodeling without neointima formation in the contralateral artery. This was associated with an increase in Tlr4 expression and EDA and Hsp60 mRNA levels. In contrast, outward remodeling was not observed after carotid ligation in Tlr4-deficient mice. CONCLUSIONS: These findings provide genetic evidence that Tlr4 is involved in outward arterial remodeling, probably through upregulation of Tlr4 and Tlr4 ligands.

Animals↗
PubMed2003

Characterizing vulnerable plaque features with intravascular elastography.

BACKGROUND: In vivo detection of vulnerable plaques is presently limited by a lack of diagnostic tools. Intravascular ultrasound elastography is a new technique based on intravascular ultrasound and has the potential to differentiate between different plaques phenotypes. However, the predictive value of intravascular elastography to detect vulnerable plaques had not been studied. METHODS AND RESULTS: Postmortem coronary arteries were investigated with intravascular elastography and subsequently processed for histology. In histology, a vulnerable plaque was defined as a plaque consisting of a thin cap (<250 microm) with moderate to heavy macrophage infiltration and at least 40% of atheroma. In elastography, a vulnerable plaque was defined as a plaque with a high strain region at the surface with adjacent low strain regions. In 24 diseased coronary arteries, we studied 54 cross sections. In histology, 26 vulnerable plaques and 28 nonvulnerable plaques were found. Receiver operator characteristic analysis revealed a maximum predictive power for a strain value threshold of 1.26%. The area under the receiver operator characteristic curve was 0.85. The sensitivity was 88%, and the specificity was 89% to detect vulnerable plaques. Linear regression showed high correlation between the strain in caps and the amount of macrophages (P<0.006) and an inverse relation between the amount of smooth muscle cells and strain (P<0.0001). Plaques, which are declared vulnerable in elastography, have a thinner cap than nonvulnerable plaques (P<0.0001). CONCLUSIONS: Intravascular elastography has a high sensitivity and specificity to detect vulnerable plaques in vitro.

Collagen↗
PubMed2003

Toll-like receptors in cardiovascular diseases.

The Toll-like receptor family recognizes mostly exogenous ligands like bacterial lipopolysaccharides or DNA and activates the inflammatory cell. Evidence is accumulating that these Toll-like receptors are important in cardiovascular pathologies. Recently, expression of Toll-like receptors in arterial and myocardial cells has been shown and mouse knockout and human studies on polymorphisms point to a role of Toll-like receptor 4 in neointima formation and atherosclerosis. It is now becoming clear that these receptors not only serve as receptors for pathogen-associated molecular patterns but are also involved in the initiation and progression of cardiovascular pathologies.

Animals↗
PubMed2003

From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part II.

Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document will focus on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.

Animals↗
PubMed2003

From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I.

Atherosclerotic cardiovascular disease results in >19 million deaths annually, and coronary heart disease accounts for the majority of this toll. Despite major advances in treatment of coronary heart disease patients, a large number of victims of the disease who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs. The recognition of the role of the vulnerable plaque has opened new avenues of opportunity in the field of cardiovascular medicine. This consensus document concludes the following. (1) Rupture-prone plaques are not the only vulnerable plaques. All types of atherosclerotic plaques with high likelihood of thrombotic complications and rapid progression should be considered as vulnerable plaques. We propose a classification for clinical as well as pathological evaluation of vulnerable plaques. (2) Vulnerable plaques are not the only culprit factors for the development of acute coronary syndromes, myocardial infarction, and sudden cardiac death. Vulnerable blood (prone to thrombosis) and vulnerable myocardium (prone to fatal arrhythmia) play an important role in the outcome. Therefore, the term "vulnerable patient" may be more appropriate and is proposed now for the identification of subjects with high likelihood of developing cardiac events in the near future. (3) A quantitative method for cumulative risk assessment of vulnerable patients needs to be developed that may include variables based on plaque, blood, and myocardial vulnerability. In Part I of this consensus document, we cover the new definition of vulnerable plaque and its relationship with vulnerable patients. Part II of this consensus document focuses on vulnerable blood and vulnerable myocardium and provide an outline of overall risk assessment of vulnerable patients. Parts I and II are meant to provide a general consensus and overviews the new field of vulnerable patient. Recently developed assays (eg, C-reactive protein), imaging techniques (eg, CT and MRI), noninvasive electrophysiological tests (for vulnerable myocardium), and emerging catheters (to localize and characterize vulnerable plaque) in combination with future genomic and proteomic techniques will guide us in the search for vulnerable patients. It will also lead to the development and deployment of new therapies and ultimately to reduce the incidence of acute coronary syndromes and sudden cardiac death. We encourage healthcare policy makers to promote translational research for screening and treatment of vulnerable patients.

Acute Disease↗
PubMed2003

Increased arterial expression of a glycosylated haptoglobin isoform after balloon dilation.

OBJECTIVE: Haptoglobin is a novel cell migration factor that is expressed in arteries after sustained flow changes and involved in arterial restructuring. Arterial restructuring is the major determinant of arterial shrinkage after balloon dilation. Although the function of extrahepatic haptoglobin expression is not yet understood, local haptoglobin expression may provide the tissue with functionally different haptoglobin due to post-translational modifications. We hypothesized that haptoglobin expression is increased during arterial restructuring after balloon dilation and compared glycosylation patterns between arterial and liver haptoglobin. METHODS: Arterial haptoglobin expression was studied in rabbits at 0, 2, 7, 14 and 28 days after balloon dilation (n=36) using real-time polymerase chain reaction, Western blotting and in situ hybridization. Two-dimensional gel electrophoresis and lectin affinity blotting were used to identify liver and arterial haptoglobin glycoforms. RESULTS: Arterial haptoglobin mRNA (5.7-fold, P=0.01) and protein levels (1.4-fold, P=0.01) were increased after balloon dilation whereas liver haptoglobin expression remained constant. Haptoglobin was expressed in the adventitia of balloon dilated rabbit arteries, which was confirmed in human atherosclerotic arteries. Comparison between liver and arterial haptoglobin demonstrated the expression of artery-specific haptoglobin glycoforms. CONCLUSIONS: This study demonstrates that arterial haptoglobin expression is increased early after balloon dilation whereas liver haptoglobin expression does not change. Furthermore, arterial haptoglobin consists of an unique set of glycoforms compared to haptoglobin produced in the liver.

Animals↗
PubMed2003

Expansive remodeling is a response of the plaque-related vessel wall in aortic roots of apoE-deficient mice: an experiment of nature.

OBJECTIVE: In the present study, we (1) evaluated the apolipoprotein E-deficient (apoE(-/-)) mouse aortic root as a model for expansive remodeling in atherosclerosis and (2) examined whether remodeling at this site was due to dilation of the vessel wall beneath or flanking the plaque. METHODS AND RESULTS: Plaque area and length of the internal elastic lamina (IEL) were measured in aortic roots of apoE(-/-) mice at 11 weeks, 6 months, and 13 months of age. Expansive remodeling, indicated by IEL lengthening exceeding that of normal growth in wild-type C57BL/6 mice, was evident at 6 months of age and showed overcompensation (luminal enlargement) by 13 months of age. When the left coronary (LC), right coronary (RC), and noncoronary (NC) sinuses of the aortic root were looked at individually, remodeling was located to the LC at 6 months of age and to the LC and RC at 13 months of age. The remodeling response was closely related to local plaque area but unrelated to plaque formation in flanking sinuses. CONCLUSIONS: The aortic root of the apoE(-/-) mouse features a consistent remodeling response. In this model, expansive remodeling was a strictly local response of the plaque-related vessel wall.

Animals↗
PubMed2003

Decorin inhibition of PDGF-stimulated vascular smooth muscle cell function: potential mechanism for inhibition of intimal hyperplasia after balloon angioplasty.

Decorin is a small proteoglycan that binds to transforming growth factor-beta (TGF-beta) and inhibits its activity. However, its interaction with platelet-derived growth factor (PDGF), involved in arterial repair after injury, is not well characterized. The objectives of this study were to assess decorin-PDGF and decorin-PDGF receptor (PDGFR) interactions, the in vitro effects of decorin on PDGF-stimulated smooth muscle cell (SMC) functions and the in vivo effects of decorin overexpression on arterial repair in a rabbit carotid balloon-injury model. Decorin binding to PDGF was demonstrated by solid-phase binding and affinity cross-linking assays. Decorin potently inhibited PDGF-stimulated PDGFR phosphorylation. Pretreatment of rabbit aortic SMC with decorin significantly inhibited PDGF-stimulated cell migration, proliferation, and collagen synthesis. Decorin overexpression by adenoviral-mediated gene transfection in balloon-injured carotid arteries significantly decreased intimal cross-sectional area and collagen content by approximately 50% at 10 weeks compared to beta-galactosidase-transfected or balloon-injured, non-transfected controls. This study shows that decorin binds to PDGF and inhibits its stimulatory activity on SMCs by preventing PDGFR phosphorylation. Decorin overexpression reduces intimal hyperplasia and collagen content after arterial injury. Decorin may be an effective therapy for the prevention of intimal hyperplasia after balloon angioplasty.

Angioplasty, Balloon↗
PubMed2003

The acute phase protein haptoglobin is locally expressed in arthritic and oncological tissues.

Haptoglobin is an acute phase protein known to be highly expressed in the liver. Recently, we showed increased local arterial haptoglobin expression after flow-induced arterial remodelling and found that haptoglobin is involved in cell migration and arterial restructuring probably through accumulation of a temporary gelatin matrix. Since cell migration and matrix turnover are important features in the pathology of arthritis and cancer, we hypothesized that haptoglobin is also locally expressed in arthritic and oncological tissues. In this study, we investigated local haptoglobin expression in arthritic rats (n = 12) using semi-quantitative PCR and Western blotting, and we studied haptoglobin mRNA localization in human kidney tumours (n = 3) using in situ hybridization. The arthritic rats demonstrated an increase of haptoglobin mRNA (2.5-fold, P < 0.001) and protein (2.6-fold, P < 0.001) in the arthritic Achilles tendon. Haptoglobin protein was also increased in the arthritic ankle (2.6-fold, P < 0.001) but not in the non-arthritic knee. In human kidney tumours, tumour and stromal cells produced haptoglobin mRNA. This study shows that the liver protein haptoglobin is, in addition to the artery, also expressed in arthritic and oncological tissues that are recognized for enhanced cell migration and matrix turnover.

Animals↗
PubMed2002

Nitric oxide synthesis is involved in arterial haptoglobin expression after sustained flow changes.

The acute phase protein haptoglobin is highly expressed in arteries after sustained flow changes and involved in cell migration and arterial restructuring. In the liver, haptoglobin expression is mainly regulated by interleukin-6 (IL-6). In the artery, shear stress and NO influence IL-6 expression. In the present study, we demonstrate that NO synthesis is involved in the regulation of arterial haptoglobin expression after sustained flow changes. Decreased haptoglobin expression after NO inhibition coincided with decreased IL-6 levels. However, IL-6 knockout mice had normal arterial haptoglobin expression levels after sustained flow changes suggesting that other mediators may provide compensatory mechanisms for the regulation of arterial haptoglobin expression.

Animals↗
PubMed2002

In vivo evidence for a role of toll-like receptor 4 in the development of intimal lesions.

BACKGROUND: Inflammation plays an important role in atherogenesis. The toll-like receptor 4 (TLR4) is the receptor for bacterial lipopolysaccharides and also recognizes cellular fibronectin and heat shock protein 60, endogenous peptides that are produced in response to tissue injury. To explore a possible role for this receptor in arterial obstructive disease, we determined the expression of TLR4 in the atherosclerotic arterial wall, including adventitia, and studied the effect of adventitial TLR4 activation on neointima formation in a mouse model. METHODS AND RESULTS: Localization of TLR4 was studied in human atherosclerotic coronary arteries by immunohistochemistry and detected in plaque and adventitia. In the adventitia, not all TLR4-positive cells colocalized with macrophages. In primary human adventitial fibroblasts, expression of TLR4 was demonstrated by immunofluorescence, Western blot, and reverse transcriptase-polymerase chain reaction. Adding lipopolysaccharide to these fibroblasts induced activation of NF-kappaB and an increase of mRNAs of various cytokines. The effect of adventitial stimulation of TLR4 was studied in a mouse model. A peri-adventitial cuff was placed around the femoral artery. Application of lipopolysaccharide between cuff and artery augmented neointima formation induced by the cuff (intimal area+/-SEM, 9134+/-1714 versus 2353+/-1076 microm(2), P<0.01). In TLR4-defective mice, application of cuff and lipopolysaccharide resulted in a smaller neointima than in wild-type mice (intimal area, 3859+/-904 microm(2), P=0.02 versus wild type). CONCLUSIONS: A functional TLR4 is expressed in human adventitial fibroblasts and macrophages. Adventitial TLR4 activation augmented neointima formation in a mouse model. These results provide evidence for a link between the immune receptor TLR4 and intimal lesion formation.

Animals↗
PubMed2002

Significance of peptidoglycan, a proinflammatory bacterial antigen in atherosclerotic arteries and its association with vulnerable plaques.

Peptidoglycan (PG) is a major component of the cell wall of gram-positive bacteria that is abundantly present in all human mucosa. PG is a functional lipopolysaccharide analog that binds to CD14 on macrophages and induces proinflammatory cytokine production and metalloproteinases. We investigated the hypothesis that bacterial PG is present in atherosclerotic tissue. In addition, plaque phenotypes were characterized in relation to presence of PG. Immunohistology of carotid (n = 15) and femoral (n = 6) endarterectomy specimens revealed the presence of PG in the cytoplasm of cells located in plaques. PG was detected in 14 of 15 carotid arteries and 5 of 6 femoral arteries. From the 14 coronary arteries, 31 atherosclerotic segments were selected. PG was detected within 19 of 31 of these coronary segments. Western blot demonstrated the presence of the toll-like receptor (TLR-2), the co-receptor for PG, in coronary artery tissue. The number of PG-containing cells in coronary arteries was significantly higher when the histologic features of plaque vulnerability were evident. Inflammation of the cap or shoulder was observed in 11 of 19 PG-positive versus 2 of 12 PG-negative segments (p = 0.023). More than 50% of the plaque area consisted of atheroma in 7 of 19 PG-positive segments and 0 of 12 PG-negative segments (p = 0.025). Heavy smooth muscle cell staining occurred in the plaque cap and shoulder in 3 of 19 PG-positive segments versus 9 of 12 PG-negative segments. Proinflammatory bacterial PG and its co-receptor have been observed in atherosclerotic arteries, in association with the vulnerable plaque phenotype.

Aged↗