CD14 promoter polymorphism (- 159C-->t) is not associated with myocardial infarction or coronary artery disease in patients with assumed high genetic risk.

OBJECTIVE: Inflammation plays a major role in the pathogenesis of coronary artery disease (CAD) and myocardial infarction (MI). CD14 is the receptor for bacterial lipopolysaccharide in monocytes and mediates the production of proinflammatory cytokines. The promoter of the CD14 gene has a polymorphic site in position - 159 (C-->T) and T-homozygotes have been shown to express higher amounts of CD14 by some investigators. We and others have found an association of the T-allele with past MI in former studies, but reports in the literature are contradictory. METHODS AND RESULTS: We investigated a study group with an assumed high genetic risk by selecting 200 patients suffering from angiographically verified CAD or MI who were younger than 50 years or who had only one or no risk factor (hypertension, smoking, elevated body mass index, impaired glucose tolerance or elevated cholesterol levels). We used 252 healthy subjects as controls. Additionally, the levels of soluble (s) CD14 in plasma and amount of membranous (m) CD14 on the surface of monocytes were determined in different genotypes. We found no association of either genotype with CAD, extent of CAD, or a history of MI. No significant correlation was found after adjustment for vascular risk factors. In addition, no significant differences in the density of monocyte mCD14 or in plasma levels of sCD14 were detectable among the various genotypes. CONCLUSIONS: The assumed weak association of the TT-genotype of the CD14 promoter polymorphism with MI could not be not established in a well-defined group of young patients with a high genetic risk. The association of the polymorphism with expression of sCD14 or mCD14 was not confirmed.

[Challenge in diabetes therapy: effects of glitazones beyond blood glucose control]. / Herausforderung Diabetestherapie: Effekte der Glitazone jenseits der Blutzuckerkontrolle.

Not just since the results of ACCORD, ADVANCE and VADT were published, it is clear that lowering blood glucose alone does not reduce the cardiovascular risk of patients with type 2 diabetes. In fact, many studies also indicate that some treatment strategies may even have adverse effects. To treat type 2 diabetes appropriately, the co-morbidities such as diabetic dyslipidaemia, hypertension or nephropathy must also be taken into account. Thiazolidinediones reduce insulin resistance thus allowing to direct the treatment of type 2 diabetes towards its pathophysiologic origin. Due to their mechanism of action, thiazolidinediones not only lower blood glucose but have also beneficial effects on inflammatory and atherogenic parameters, blood pressure and microalbuminuria. Furthermore pioglitazone improves dyslipidaemia and reduces mortality, myocardial infarction and stroke in high risk patients. Effects of rosiglitazone on the cardiovascular risk are yet unclear. Numerous studies document the efficacy and safety of thiazolidinediones and provide a basis for an evidence-based therapeutic approach beyond blood glucose control.

Gelatinase B C(-1562)T polymorphism in relation to ischaemic heart disease.

OBJECTIVE: Matrix metalloproteinases, such as gelatinase B, are important in connective tissue remodelling processes associated with atherogenesis and plaque rupture. The T allele of the gelatinase B C((-1562)) T polymorphism has been reported to be associated with an almost 2-fold increase in promoter activity and with the extent of coronary artery disease (CAD). The aim of this study was to analyse the relation of this gene variation to the risk and severity of CAD and the risk of myocardial infarction (MI). MATERIAL AND METHODS: This case-control study comprised 535 healthy controls and 2731 participants who had undergone coronary angiography. RESULTS: In the total sample, the gelatinase B promoter polymorphism was not associated with the risk of CAD and MI or with the extent of CAD defined either by the number of diseased coronary arteries or--in patients with coronary angiography--by a score for coronary heart disease (CHD) according to the Gensini score. However, patients with TT genotype had higher CHD scores than the other genotypes in subgroups of individuals with high apolipoprotein B levels, high lipoprotein (a) plasma concentrations and high fibrinogen levels, or with combinations of increased levels of these coronary risk factors. These observations were made in the entire sample of individuals with coronary angiography and in the population of patients with documented CHD. CONCLUSIONS: Obviously, the gelatinase B C((-1562))T gene polymorphism is not a risk indicator for CAD and MI. With respect to the extent of CHD, the impact of this gene variation may be restricted to individuals with high apolipoprotein B, lipoprotein (a) and/or fibrinogen levels.

Statins differ in their ability to block NF-kappaB activation in human blood monocytes.

OBJECTIVE: The benefits of statin therapy in cardiovascular medicine are ascribed to its lipid-lowering effect as well as its anti-inflammatory properties. Whereas all statins have been shown to reduce cholesterol plasma levels, their effect on inflammatory markers has been inconsistent. Here, we show that statins differ markedly in their effectiveness in preventing activation of NF-kappaB, a transcription factor involved in the activation of immediately early genes during inflammation. METHODS: Six statins (atorvastatin (Atv), cerivastatin (Cer), fluvastatin (Flu), lovastatin (Lov), pravastatin (Pra), simvastatin (Sim)) were tested for their ability to influence the induction of NF-kappaB in human monocytes (Mo) during inflammation. Mo isolated from healthy blood donors were incubated with LPS (10 microg/ml) in the presence and absence of statin (0.001-5 microM). NF-kappaB binding activity (EMSA), degradation and phosphorylation of the inhibitor protein IkappaB-alpha (Western blotting), tissue factor (TF) mRNA (rtPCR), and TF activity (clotting assay) were analyzed. RESULTS: All statins inhibited LPS-induced NF-kappaB binding activity in Mo in a dose-dependent manner. The inhibitory effect was due to reduced phosphorylation and degradation of the NF-kappaB inhibitor protein IkappaB, and was primarily dependent on the absence of mevalonate. Whilst this effect appeared with all statins, there were marked differences in the degree of inhibition between the statins. Cer (45 +/- 9% inhibition, p < 0.05) was 9-fold more effective in reducing NF-kappaB activation than Flu (5 +/- 10% inhibition). The differences in the potency of statins (Cer > Atv > Sim > Pra > Lov > Flu) were also reflected at the transcriptional level and the protein level of NF-kappaB controlled tissue factor expression. CONCLUSIONS: The finding that statins differ in their potency in interfering with the activation of NF-kappaB signaling in human monocytes further supports the hypothesis that some statins inhibit the inflammatory response more than others.

[Prevalence and significance of coronary collateral circulation in patients with acute myocardial infarct]. / Prävalenz und Bedeutung der koronaren Kollateralzirkulation bei Patienten mit akutem Myokardinfarkt.

UNLABELLED: Angiograms from consecutive and unselected patients with acute myocardial infarction were studied with respect to the prevalence as well as the significance of coronary collateral circulation to myocardium distal to the acute coronary occlusion. METHODS: Coronary angiograms were obtained from 700 consecutive and unselected patients with an acute transmural infarction within 3.7 +/- 3 hours (0.5-12) of symptom onset. No patient had undergone i.v. thrombolysis prior to angiography. Complete and acute vessel occlusion was found in 626/700 patients (89%). Coronary collaterals were detected and graded using Rentrop's classification. The grade of collateral circulation was related to the clinical course after 30 days and to the global and regional left ventricular wall motion. RESULTS: Collaterals were found in 334 patients (69%); 242 patients (38%) had collateral flow grade 2 or 3. Collaterals were demonstrated more frequently in women vs men and in patients with multivessel disease. The prevalence of collaterals was unrelated to age and the presence of diabetes mellitus. Patients who had angiography within 3 hours of symptom onset had collaterals detected less frequently than patients who had angiography beyond 6 hours (66% vs 75%, p < 0.05). No collaterals were found in 17/37 patients (47%) in cardiogenic shock and inferior MI but in only 30/164 patients (18%, p < 0.01) without shock. Global and regional left ventricular wall motion after 2 weeks was unrelated to the degree of coronary collateral circulation during acute myocardial infarction. CONCLUSION: Collateral circulation to myocardium distal to an acutely occluded coronary artery is detected in 2/3 patients during the acute infarct phase. The absence of collaterals is related to the early occurrence of cardiogenic shock in patients with inferior MI but not to the presence of diabetes mellitus. After direct angioplasty of the infarct vessel, the protective effects of coronary collaterals on chronic LV function remain uncertain.

Opposite regulation of tissue factor expression by calcineurin in monocytes and endothelial cells.

Tissue factor (TF), the primary initiator of blood coagulation with structural homology to the cytokine receptor family, has been implicated in various vascular processes including metastasis, angiogenesis, and atherosclerosis. Within the vasculature, monocytes and endothelial cells (EC) can be activated to synthesize TF depending on the induction of NF-kappaB. Despite the undisputed value of cyclosporin A (CsA) as an immunosuppressant, problems have emerged due to induction of vascular changes by a poorly understood mechanism. We demonstrate that CsA has opposite effects on TF gene expression, inhibiting NF-kappaB-mediated TF gene transcription in monocytes but enhancing it in EC. To test whether CsA binding proteins (cyclophilins) can mediate these CsA effects we used a nonimmunosuppressant analog of CsA that binds to cyclophilins but does not inhibit the Ca2+/calmodulin-dependent phosphatase calcineurin (Cn). This drug lacked regulatory function for NF-kappaB and TF expression suggesting that Cn is responsible for the inverse gene regulation. The key function of Cn was supported by experiments demonstrating that other phosphatase inhibitors also either positively or negatively regulated NF-kappaB in monocytes and EC. Calcineurin was demonstrated to regulate NF-kappaB activation at the level of IkappaBalpha degradation, because agonist-induced phosphorylation and subsequent degradation of IkappaBalpha is prevented by Cn inhibitors in monocytes but enhanced in EC. These data identify Cn as an opposite regulator in generating transcriptionally active NF-kappaB, and they confirm the presumption that the ability of Cn to participate in NF-kappaB transactivation is not T cell specific.

The paraoxonase Leu-Met54 and Gln-Arg191 gene polymorphisms are not associated with the risk of coronary heart disease.

BACKGROUND: Evidence has been presented that gene polymorphisms (PON54 L/M, PON191 Q/R) of paraoxonase are risk factors of coronary heart disease. RESULTS: We determined both PON genotypes in 535 male individuals who were free of vascular disease and in 2249 male subjects who underwent coronary angiography, and analysed the relation of both gene variations to CAD and MI. Both gene polymorphisms were in linkage disequilibrium (P<0.0001). Coronary artery disease: the PON54 gene polymorphism was not associated with an increased risk of CAD. In the total sample and also in younger subjects, an association of the PON191 gene variation with the risk of CAD was not detected when the control group of individuals without coronary heart disease was compared with patients with at least one diseased vessel (verified by coronary angiography). In individuals younger than 62 years, a moderate increase in the relative risk of CAD associated with the PON191 R allele (1.45 (1. 08-1.95); P=0.015) were found, when subjects without vessel disease (verified by coronary angiography) were compared with CAD patients. Myocardial infarction: an association of the PON54 gene variation with MI was not detected when the control group of individuals without coronary heart disease were compared with patients with at least one MI. A marginal increase in the risk of MI associated with the PON54 LL genotype (OR 1.27 (1.05-1.51); P=0.011) were detected when patients without MI but with coronary angiography were compared with MI positive patients. Subgroup analyses of low- and high-risk populations did not reveal any association of both PON gene polymorphisms with CAD or MI. CONCLUSION: The present findings do not strengthen the hypothesis that the paraoxonase gene polymorphisms are independently associated with coronary heart disease indicating that these gene variations are of little usefulness as genetic markers of cardiovascular disease.

[Symptomatic true aneurysm of a venous bypass with compression of the right atrium]. / Symptomatisches echtes Aneurysma eines Venenbypass mit Kompression des rechten Vorhofes.

A symptomatic true aneurysm of a saphenous vein graft to the right coronary artery in a female patient twelve years after bypass surgery is presented. Beating heart surgery included resection of the aneurysmatic saphenous vein graft, reconstruction of the right atrium and coronary artery bypass grafting to the right coronary artery. The symptoms of aneurysms of vein grafts, the diagnostic procedures and the surgical treatment are discussed.

Hirudin reduces tissue factor expression and attenuates graft arteriosclerosis in rat cardiac allografts.

BACKGROUND-Intravascular clotting has been implicated in the pathogenesis of cardiac allograft vasculopathy (CAV). We previously identified the expression of tissue factor (TF), the primary cellular initiator of blood coagulation, within the coronary intima, which was associated with neointimal thickening. In the present study, the effect of recombinant hirudin on CAV was assessed in Lewis to Fisher rat heterotopic cardiac allografts. METHODS AND RESULTS-Transplant recipients were randomized to a control group (n=10) and a hirudin-treated group (n=12; 2 mg. kg(-1). d(-1) SC). Histological evaluations of rejection, CAV, and TF staining were performed 120 days after transplantation. No significant differences were observed between the 2 groups with respect to the degree of rejection. Hirudin significantly (P<0.05) suppressed the development of CAV in the graft microvessels, but it was less effective in large coronary arteries. Graft intimal cells, isolated by laser-assisted cell picking, showed a marked upregulation of TF gene transcription, which was prevented by hirudin (P<0.01). As demonstrated by immunohistochemistry and quantitative analyses of TF mRNA levels by real-time polymerase chain reaction, hirudin treatment resulted in a significant reduction of TF protein and mRNA expression (P<0.001). CONCLUSIONS-Treatment with hirudin in this rat cardiac transplant model inhibited TF expression and decreased neointimal hyperplasia. These results suggest that TF inhibition by hirudin, in addition to its direct effect on thrombin, may attenuate the hypercoagulable state and prevent the development of CAV at least in restricted sites of the graft coronary vasculature.

Chlamydia pneumoniae infection is not an independent risk factor for arterial disease.

Appreciation of atherosclerosis as an infectious disease has fostered interest in the role that Chlamydia pneumoniae may play in atheroma development. Although data from seroepidemiological and experimental studies have established an association between the pathogen and atherosclerosis, little is known about how the organism contributes to lesion development. Atherosclerosis is a complex disease process and the role of any pathogen must be considered in the context of other risk factors. Here we focus on the relationship between Chlamydia pneumoniae and conventional risk factors for atherosclerosis. There is evidence for a strong association between chronic infection with Chlamydia pneumoniae and smoking as well as high serum cholesterol. It is concluded from the present data that chronic infection with the pathogen is not an independent risk factor for atherosclerosis.

Simvastatin attenuates vascular hypercoagulability in cardiac transplant recipients.

BACKGROUND: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to reduce cardiac allograft failure and to lower the incidence of transplant coronary artery disease. These effects result from as yet unknown mechanisms not clearly attributable to lipid lowering. We here report that low-dose simvastatin treatment inhibits excessive expression of monocyte tissue factor (TF) and reduces the persistent hypercoagulability state seen in cardiac transplant recipients. METHODS: Fifteen consecutive heart transplant recipients receiving standard oral immunosuppression were newly assigned to a 10 mg daily simvastatin therapy. Levels of TF activity in both unstimulated and lipopolysaccharide-stimulated peripheral blood mononuclear cells drawn from transplant recipients before and under simvastatin therapy were evaluated by one-stage clotting assay. RESULTS: Monocyte TF activity was found to be significantly increased in cardiac transplant recipients when compared with healthy controls. Excessive monocyte procoagulant activity was reduced in cardiac transplant recipients during simvastatin treatment. This effect occurred independently of the reduction of serum low-density lipoprotein cholesterol. As demonstrated by reverse transcriptase-polymerase chain reaction, monocyte TF reduction by simvastatin, observed in 13 of the 15 transplant recipients investigated, could be ascribed to an inhibition of monocyte TF gene transcription. The reduction of monocyte TF activity during treatment with simvastatin paralleled with the normalization of elevated levels of thrombin-antithrombin complex, prothrombin fragment F1+2, and D-dimer, which are markers of thrombin and fibrin formation indicating coagulation activation after cardiac transplantation. CONCLUSION: Inhibition of monocyte TF expression and attenuation of the persistent hypercoagulable state observed in cardiac transplant recipients during treatment with simvastatin may represent an important mechanism by which HMG-CoA reductase inhibitors protect against the development of transplant coronary artery disease.

Antibody response to the 60-kDa heat-shock protein of Chlamydia pneumoniae in patients with coronary artery disease.

Serum specimens from 752 individuals undergoing coronary arteriography were examined for antibodies to Chlamydia pneumoniae. Patients with coronary artery disease (CAD) were more likely to have IgG antibodies to C. pneumoniae than were individuals without CAD (60% vs. 52%; P=.007; odds ratio, 1.8; 95% confidence interval, 1. 17-2.77). Antibodies to recombinant hsp60 of C. pneumoniae were found with nearly the same frequency in patients with CAD and individuals without CAD (29% vs. 30%; P=.751). There was no association between chlamydial hsp60 antibodies and the severity of CAD or a previous myocardial infarction. Patient sera reacted most frequently to C. pneumoniae proteins of 17, 38, 40, 58, and 60/62 kDa. Reactivity to these proteins was not different between patients with and without CAD. Study results indicate that neither antibodies to chlamydial hsp60 nor antibodies to other C. pneumoniae proteins are useful for discriminating between seropositive patients with and without CAD.

The impact of the glycoprotein Ia collagen receptor subunit A1648G gene polymorphism on coronary artery disease and acute myocardial infarction.

Platelet glycoprotein (GP) Ia is the major receptor for collagen and plays an important role in platelet adhesion and aggregation. Different gene polymorphisms have been identified that induce either various expression levels (C807T) or alterations of the tertiary structure (A1648G) of GPIa. Previously, we could demonstrate an association of the GPIa C807T dimorphism with nonfatal myocardial infarction. We have now analysed the influence of the GPIa A1648G (Br, HPA-5) dimorphism on the risk of coronary artery disease (CAD) and acute myocardial infarction (AMI). DNA samples from 2163 male Caucasian patients who underwent coronary angiography were genotyped by polymerase chain reaction and restriction fragment length analysis. The relation of the GPIa A1648G dimorphism to the extent of CAD was determined by multiple regression analysis with adjustment for coronary risk factors. Odds ratios (OR) as an estimate of relative risk of CAD and AMI and two-tailed p-values were calculated by multiple logistic regression. In the total study sample, no association was detected between the A1648G dimorphism and CAD or AMI. However, upon analysis of low-risk patient subgroups we found an association of the GPIa A1648G polymorphism with the risk and the extent of CAD (patients with high apoAI/apoB ratio: OR 0.59, p = 0.0090; non- and ex-smokers: OR 0.66, p = 0.0131; both inclusion criteria: OR 0.44, p = 0.0003). The relative frequency of the A1648 allele was higher in controls whereas the GG1648 genotype was overrepresented in patients with CAD. This association was also detectable when individuals with low expression levels of GPIa (C807 homozygotes) were analysed (patients with high apoAI/apoB ratio: OR 0.44, p = 0.0045; non- and ex-smokers: OR 0.61, p = 0.0370). Our findings indicate that the A1648G polymorphism of the platelet collagen receptor plays a role in CAD in well defined patient groups.

Staphylococcal alpha-toxin provokes coronary vasoconstriction and loss in myocardial contractility in perfused rat hearts: role of thromboxane generation.

BACKGROUND: Cardiac performance is severely depressed in septic shock. Endotoxin has been implicated as the causative agent in Gram-negative sepsis, but similar abnormalities are encountered in Gram-positive sepsis. We investigated the influence of the major exotoxin of Staphylococcus aureus, staphylococcal alpha-toxin, in isolated perfused rat hearts. METHODS AND RESULTS: Alpha-toxin 0.25 to 1 microg/mL caused a dose-dependent increase in coronary perfusion pressure that more than doubled. In parallel, we noted a decrease in left ventricular developed pressure and the maximum rate of left ventricular pressure rise (dP/dt(max)), dropping to a minimum of <60% of control. These changes were accompanied by a liberation of thromboxane A(2) and prostacyclin into the coronary effluent. The release of creatine kinase, lactate dehydrogenase, potassium, and lactate did not surpass control heart values, and leukotrienes were also not detected. Indomethacin, acetylsalicylic acid, and the thromboxane receptor antagonist daltroban fully blocked the alpha-toxin-induced coronary vasoconstrictor response and the decrease in left ventricular developed pressure and dP/dt(max), whereas the lipoxygenase inhibitor nordihydroguaiaretic acid, the platelet activating factor antagonist WEB 2086, and the alpha-adrenergic antagonist phentolamine were entirely ineffective. Inhibition of nitric oxide synthase even enhanced the alpha-toxin-induced increase in coronary perfusion pressure and the loss in myocardial performance. CONCLUSIONS: Purified staphylococcal alpha-toxin provokes coronary vasoconstriction and loss in myocardial contractility. The responses appear to be largely attributable to the generation of thromboxane and are even enhanced when the endogenous nitric oxide synthesis is blocked. Bacterial exotoxins, such as staphylococcal alpha-toxin, may thus be implicated in the loss of cardiac performance encountered in Gram-positive septic shock.

Monocyte tissue factor expression is enhanced in women who smoke and use oral contraceptives.

The association between use of oral contraceptives (OCs) and increased risk of thromboembolic disease has been firmly established. This risk increases when use of OCs is combined with cigarette smoking. The cellular mechanism favoring an hypercoagulable state under these behaviours is not known. Circulating monocytes are potent activators of the coagulation cascade through their ability to synthesize procoagulant tissue factor (TF). In the present study we report that monocyte TF expression is increased in women who use OCs and smoke. We studied monocyte TF expression in 4 groups of healthy pre-menopausal women (n = 15 each): (1) non-smoking OC non-users, (2) nonsmoking current OC users, (3) smoking OC non-users and (4) smoking OC users. TF expression was assessed on both mRNA and protein levels in unstimulated and LPS-stimulated cells. Transcriptional activation of the TF gene was assessed by analysis of the transcription factor NF-kappaB and its inhibitor molecule IkappaBalpha. Monocyte TF generation was significantly higher in OC users than in women who did not use OCs. Enhanced monocyte TF generation was also observed in smoking women when compared to non-smokers. Strongest monocyte TF expression occurred in women with combined smoking and use of OCs. The enhanced TF expression in monocytes from women using OCs or smoking was based on an increased TF gene transcription following activation of NF-kappaB. Experiments on cultured monocytes/macrophages demonstrated enhanced IkappaBalpha degradation in the presence of estradiol, suggesting that a direct hormone effect is responsible for the observed increase in monocyte TF expression. This study demonstrates that use of OCs and smoking is associated with an increase in monocyte TF expression in pre-menopausal women. Aberrant TF expression by blood monocytes may favour intravascular clotting activation in women with OC therapy. The further enhancement of TF activity observed in women who smoke and use OCs may explain the synergistic effect of smoking on risk of thromboembolic events associated with contraceptive use.

[Acute myocardial infarction late after coronary artery bypass grafting: angiographic findings and results of an invasive approach]. / Akuter Myokardinfarkt spät nach aortokoronarer Bypassoperation: Angiographische Befunde und klinische Ergebnisse eines invasiven Vorgehens.

Patients who have undergone coronary artery bypass grafting may develop acute myocardial infarction late after surgery. It is not exactly known in these patients whether acute infarction is predominantly caused by occlusion of bypass or native vessels. Also, there is no systematic and prospective data available with respect to an invasive, revascularizing therapeutic approach. Therefore, acute coronary angiograms were obtained in 21 consecutive patients with acute infarctions and remote bypass grafting to elucidate mechanisms causing myocardial infarction in these patients, and to assess results of catheter-based recanalization. Infarction was causes by acute graft occlusion in 12/21 patients. Fibrinolysis and/or PTCA of grafts was successful in 6/8 attempts, direct PTCA of a native vessel was effective in 1/2 patients, 1 patient underwent emergency re-CABG, and another patient was treated noninvasively. Occlusion of native, ungrafted vessel caused infarction in 9 patients. Direct PTCA of native vessels was effective in 6/7 of those patients, 1 patient had re-CABG, and another patients was treated non-invasively. Together, catheter-based recanalization was obtained in 13/17 attempts. Thirty-day and 1 year mortality (after discharge) was 5% (1/21 patients) and 12%, respectively. Predischarge ejection fraction was 46%. In conclusion, acute occlusion of bypass grafts is responsible for about half of all cases of myocardial infarction in patients late after surgery. Direct angiography and individually tailored catheter-based recanalization in patients with acute myocardial infarction late after surgery yield promising results.

3-deazaadenosine prevents adhesion molecule expression and atherosclerotic lesion formation in the aortas of C57BL/6J mice.

Adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) play an important role during the development of atherosclerosis. 3-Deazaadenosine (c(3)Ado), an adenosine analogue, inhibits endothelial-leukocyte adhesion and ICAM-1-expression in vitro. We hypothesized that c(3)Ado is able to prevent the expression of adhesion molecules and atherosclerotic lesion formation in female C57BL/6J mice. The animals were placed on an atherogenic diet with or without c(3)Ado for 9 weeks. Frozen cross sections of the proximal ascending aorta just beyond the aortic sinus were stained with oil red O, hematoxylin, and elastic van Gieson's stains and were analyzed by computer-aided planimetry for fatty plaque formation and neointimal proliferation. Monoclonal antibodies against CD11b (macrophages), VCAM-1, and ICAM-1 were used for immunohistochemistry. Mice on the atherogenic diet demonstrated multiple (5.4+/-1.6 per animal) lesions covering 3.4+/-2.8% of the endothelium and a marked neointima when compared with control mice (4501+/-775 versus 160+/-38 microm(2), P<0.001). Mice on the cholesterol-rich diet without c(3)Ado showed strong endothelial coexpression of ICAM-1 and VCAM-1. Moreover, there was a 10-fold increase in monocyte accumulation on the endothelial surface (33. 3+/-4.9 versus 3.8+/-1.2, P<0.004). In contrast, in mice treated with c(3)Ado, expression of ICAM-1 and VCAM-1 as well as monocyte adhesion and infiltration were almost completely inhibited. Furthermore, these mice did not show any fatty streak formation or neointima formation (125+/-32 microm(2)). Our results demonstrate that c(3)Ado can inhibit diet-induced fatty streak formation and the expression of endothelial ICAM-1 and VCAM-1 in C57BL/6J mice. This may provide a novel pharmacological approach in the prevention and treatment of atherosclerosis.