Donor MHC and adhesion molecules in transplant arteriosclerosis.
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Transplant-associated arteriosclerosis remains an obstacle to long-term graft survival. To determine the contribution to transplant arteriosclerosis of MHC and adhesion molecules from cells of the donor vasculature, we allografted carotid artery loops from six mutant mouse strains into immunocompetent CBA/CaJ recipients. The donor mice were deficient in either MHC I molecules or MHC II molecules, both MHC I and MHC II molecules, the adhesion molecule P-selectin, intercellular adhesion molecule (ICAM)-1, or both P-selectin and ICAM-1. Donor arteries in which ICAM-1, MHC II, or both MHC I and MHC II were absent showed reductions in neointima formation of 52%, 33%, and 38%, respectively, due primarily to a reduction in smooth muscle cell (SMC) accumulation. In P-selectin-deficient donor arteries, neointima formation did not differ from that in controls. In donor arteries lacking both P-selectin and ICAM-1, the size of the neointima was similar to that in those lacking ICAM-1 alone. In contrast, neointima formation increased by 52% in MHC I-deficient donor arteries. The number of CD4-positive T cells increased by 2.8-fold in MHC I-deficient arteries, and that of alpha-actin-positive SMCs by twofold. These observations indicate that ICAM-1 and MHC II molecules expressed in the donor vessel wall may promote transplant-associated arteriosclerosis. MHC I molecules expressed in the donor may have a protective effect. (+info)
Blocking very late antigen-4 integrin decreases leukocyte entry and fatty streak formation in mice fed an atherogenic diet.
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Atherosclerotic lesion development is characterized by the recruitment of leukocytes, principally monocytes, to the vessel wall. Considerable interest has been focused on the adhesion molecule(s) involved in leukocyte/endothelial interactions. The goal of the present study was to determine the role of the very late antigen-4 (VLA-4) integrin/ligand interaction in fatty streak development using murine models. Because alpha4 null mice are not viable, a peptidomimetic was used to block VLA-4-mediated leukocyte binding. The ability of a synthetic peptidomimetic of connecting segment-1 (CS-1 peptide) to block the recruitment of leukocytes and the accumulation of lipid in the aortic sinus of either wild-type mice (strain C57BL/6J) or mice with a low-density lipoprotein null mutation (LDLR-/-) maintained on an atherogenic diet was assessed. The active (Ac) CS-1 peptide or scrambled (Sc) CS-1 peptide was delivered subcutaneously into mice using a mini osmotic pump. Mice were exposed to the peptide for 24 to 36 hours before the onset of the atherogenic diet. In C57BL/6J mice, leukocyte entry into the aortic sinus, as assessed by en face preparations, was inhibited by the active peptide (Ac=28+/-4, Sc=54+/-6 monocytes/valve; P=0.004). Additionally, frozen sections stained with Oil Red O were analyzed to assess lipid accumulation in the aortic sinus. C57BL/6J mice that received the (Ac) compound demonstrated significantly reduced lesion areas as compared with mice that received the (Sc) peptide (Ac=4887+/-4438 microm2, Sc=15 009 +/-5619 microm2; P<0.0001). In a separate study, LDLR-/- mice were implanted with pumps containing either the (Ac) or (Sc) peptide before initiation of the atherogenic diet. Because LDLR-/- mice fed a chow diet displayed small lesions at 14 weeks, the effects of the peptide seen in these animals represented a change in early lipid accumulation rather than initiation. By using whole-mount preparations, the (Ac) but not the (Sc) peptide significantly reduced the area of lipid accumulation in the aortic sinus, resulting in an approximate 66% decrease. Plasma analysis from all studies revealed concentrations of peptide to be present at levels previously determined by in vitro analysis to block adhesion. (Ac) CS-1 peptide, which blocks VLA-4 on the leukocyte surface, is effective in reducing leukocyte recruitment and lipid accumulation in the aortic sinus. The present study provides in vivo evidence that the VLA-4 integrin plays an important role in the initiation of the atherosclerotic lesion and lipid accumulation, and it suggests a potential therapeutic strategy for this disease. (+info)
Prevalence of peripheral arterial disease and associated risk factors in American Indians: the Strong Heart Study.
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Studies of peripheral arterial disease (PAD) in minority populations provide researchers with an opportunity to evaluate PAD risk factors and disease severity under different types of conditions. Examination 1 of the Strong Heart Study (1989-1992) provided data on the prevalence of PAD and its risk factors in a sample of American Indians. Participants (N = 4,549) represented 13 tribes located in three geographically diverse centers in the Dakotas, Oklahoma, and Arizona. Participants in this epidemiologic study were aged 45-74 years; 60% were women. Using the single criterion of an ankle brachial index less than 0.9 to define PAD, the prevalence of PAD was approximately 5.3% across centers, with women having slightly higher rates than men. Factors significantly associated with PAD in univariate analyses for both men and women included age, systolic blood pressure, hemoglobin A1c level, albuminuria, fibrinogen level, fasting glucose level, prevalence of diabetes mellitus, and duration of diabetes. Multiple logistic regression analyses were used to predict PAD for women and men combined. Age, systolic blood pressure, current cigarette smoking, pack-years of smoking, albuminuria (micro- and macro-), low density lipoprotein cholesterol level, and fibrinogen level were significantly positively associated with PAD. Current alcohol consumption was significantly negatively associated with PAD. In American Indians, the association of albuminuria with PAD may equal or exceed the association of cigarette smoking with PAD. (+info)
Chlamydia pneumoniae and atherosclerosis.
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OBJECTIVE: To review the literature for evidence that chronic infection with Chlamydia pneumoniae is associated with atherosclerosis and acute coronary syndromes. DATA SOURCES: MEDLINE and Institute of Science and Information bibliographic databases were searched at the end of September 1998. Indexing terms used were chlamydi*, heart, coronary, and atherosclerosis. Serological and pathological studies published as papers in any language since 1988 or abstracts since 1997 were selected. DATA EXTRACTION: It was assumed that chronic C pneumoniae infection is characterised by the presence of both specific IgG and IgA, and serological studies were examined for associations that fulfilled these criteria. Pathological studies were also reviewed for evidence that the presence of C pneumoniae in diseased vessels is associated with the severity and extent of atherosclerosis. DATA SYNTHESIS: The majority of serological studies have shown an association between C pneumoniae and atherosclerosis. However, the number of cases in studies that have reported a positive association when using strict criteria for chronic infection is similar to the number of cases in studies which found no association. Nevertheless, the organism is widely found in atherosclerotic vessels, although it may not be at all diseased sites and is not confined to the most severe lesions. Rabbit models and preliminary antibiotic trials suggest that the organism might exacerbate atherosclerosis. CONCLUSION: More evidence is required before C pneumoniae can be accepted as playing a role in atherosclerosis. Although use of antibiotics in routine practice is not justified, large scale trials in progress will help to elucidate the role of C pneumoniae. (+info)
Expression and cellular localization of the CC chemokines PARC and ELC in human atherosclerotic plaques.
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Local immune responses are thought to play an important role in the development of atherosclerosis. Histological studies have shown that human atherosclerotic lesions contain T lymphocytes throughout all stages of development, many of which are in an activated state. A number of novel CC chemokines have been described recently, which are potent chemoattractants for lymphocytes: PARC (pulmonary and activation-regulated chemokine), ELC (EBI1-ligand chemokine), LARC (liver and activation-regulated chemokine), and SLC (secondary lymphoid-tissue chemokine). Using reverse transcriptase-polymerase chain reaction and in situ hybridization, we have found gene expression for PARC and ELC but not for LARC or SLC in human atherosclerotic plaques. Immunohistochemical staining of serial plaque sections with specific cell markers revealed highly different expression patterns of PARC and ELC. PARC mRNA was restricted to CD68+ macrophages (n = 14 of 18), whereas ELC mRNA was widely expressed by macrophages and intimal smooth muscle cells (SMC) in nearly all of the lesions examined (n = 12 of 14). ELC mRNA was also found to be expressed in the medial SMC wall of highly calcified plaques (n = 4). Very low levels of ELC mRNA expression could also be detected in normal mammary arteries but no mRNA expression for PARC was detected in these vessels (n = 4). In vitro, ELC mRNA was found to be up-regulated in aortic SMC stimulated with tumor necrosis factor-a and interferon-gamma but not in SMC stimulated with serum. Both PARC and ELC mRNA were expressed by monocyte-derived macrophages but not monocytes. The expression patterns of PARC and ELC mRNA in human atherosclerotic lesions suggest a potential role for these two recently described CC chemokines in attracting T lymphocytes into atherosclerotic lesions. (+info)
Suppression of atherosclerotic development in Watanabe heritable hyperlipidemic rabbits treated with an oral antiallergic drug, tranilast.
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BACKGROUND: Inflammatory and immunological responses of vascular cells have been shown to play a significant role in the progression of atheromatous formation. Tranilast [N-(3,4-dimethoxycinnamoyl) anthranillic acid] inhibits release of cytokines and chemical mediators from various cells, including macrophages, leading to suppression of inflammatory and immunological responses. This study tested whether tranilast may suppress atheromatous formation in Watanabe heritable hyperlipidemic (WHHL) rabbits. METHODS AND RESULTS: WHHL rabbits (2 months old) were given either 300 mg x kg-1 x d-1 of tranilast (Tranilast, n=12) or vehicle (Control, n=13) PO for 6 months. Tranilast treatment was found to suppress the aortic area covered with plaque. Immunohistochemical analysis showed that there was no difference in the percentage of the RAM11-positive macrophage area and the frequency of CD5-positive cells (T cells) in intimal plaques between Tranilast and Control. Major histocompatibility complex (MHC) class II expression in macrophages and interleukin-2 (IL-2) receptor expression in T cells, as markers of the immunological activation in these cells, was suppressed in atheromatous plaque by tranilast treatment. Flow cytometry analysis of isolated human and rabbit peripheral blood mononuclear cells showed that an increase in expression both of MHC class II antigen on monocytes by incubation with interferon-gamma and of IL-2 receptor on T cells by IL-2 was suppressed by the combined incubation with tranilast. CONCLUSIONS: The results indicate that tranilast suppresses atherosclerotic development partly through direct inhibition of immunological activation of monocytes/macrophages and T cells in the atheromatous plaque. (+info)
Expression of stromelysin-3 in atherosclerotic lesions: regulation via CD40-CD40 ligand signaling in vitro and in vivo.
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Stromelysin-3 is an unusual matrix metalloproteinase, being released in the active rather than zymogen form and having a distinct substrate specificity, targeting serine proteinase inhibitors (serpins), which regulate cellular functions involved in atherosclerosis. We report here that human atherosclerotic plaques (n = 7) express stromelysin-3 in situ, whereas fatty streaks (n = 5) and normal arterial specimens (n = 5) contain little or no stromelysin-3. Stromelysin-3 mRNA and protein colocalized with endothelial cells, smooth muscle cells, and macrophages within the lesion. In vitro, usual inducers of matrix metalloproteinases such as interleukin-1, interferon-gamma, or tumor necrosis factor alpha did not augment stromelysin-3 in vascular wall cells. However, T cell-derived as well as recombinant CD40 ligand (CD40L, CD154), an inflammatory mediator recently localized in atheroma, induced de novo synthesis of stromelysin-3. In addition, stromelysin-3 mRNA and protein colocalized with CD40L and CD40 within atheroma. In accordance with the in situ and in vitro data obtained with human material, interruption of the CD40-CD40L signaling pathway in low density lipoprotein receptor-deficient hyperlipidemic mice substantially decreased expression of the enzyme within atherosclerotic plaques. These observations establish the expression of the unusual matrix metalloproteinase stromelysin-3 in human atherosclerotic lesions and implicate CD40-CD40L signaling in its regulation, thus providing a possible new pathway that triggers complications within atherosclerotic lesions. (+info)
High-resolution intravascular magnetic resonance imaging: monitoring of plaque formation in heritable hyperlipidemic rabbits.
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BACKGROUND: The individual makeup of atherosclerotic plaque has been identified as a dominant prognostic factor. With the use of an intravascular magnetic resonance (MR) catheter coil, we evaluated the effectiveness of high-resolution MR in the study of the development of atherosclerotic lesions in heritable hyperlipidemic rabbits. METHODS AND RESULTS: Sixteen hyperlipidemic rabbits were investigated at the ages of 6, 12, 24, and 36 months. The aorta was studied with digital subtraction angiography and high-resolution MR with the use of a surface coil and an intravascular coil that consisted of a single-loop copper wire integrated in a 5F balloon catheter. Images were correlated with histological sections regarding wall thickness, plaque area, and plaque components. Digital subtraction angiography revealed no abnormalities in the 6- and 12-month-old rabbits and only mild stenoses in the 24- and 36-month-old rabbits. High-resolution imaging with surface coils resulted in an in-plane resolution of 234x468 microm. Delineation of the vessel wall was not possible in younger rabbits and correlated only poorly with microscopic measurements in the 36-month-old rabbits. Intravascular images achieved an in-plane resolution of 117x156 microm. Increasing thickness of the aortic wall and plaque area was observed with increasing age. In the 24- and 36-month-old animals, calcification could be differentiated from fibrous and fatty tissue on the basis of the T2-fast spin echo images, as confirmed by histological correlation. CONCLUSIONS: Atherosclerotic evolution of hyperlipidemic rabbits can be monitored with high-resolution intravascular MR imaging. Image quality is sufficient to determine wall thickness and plaque area and to differentiate plaque components. (+info)