Atherosclerotic Formation Research Articles

Abstract 334: Complementary Atherosclerosis Prophylaxis in Patients After Coronary Bypass Surgery

Background and purpose: Atherosclerotic coronary arteries can be well-treated with innovative medicaments, through PCI or by aortocoronary bypasses. Some of the stents and bypasses close again in spite of blood-thinning. We examined in a clinical pilot study of 8 patients who had undergone a CABG operation whether atherosclerosis prophylaxis can be practised through an additional phytochemical approach with ginkgo (EGb 761, 2 × 120 mg/d). Furthermore, our trial aimed to inquire whether the bypasses remain open. Methods: As a biomarker for plaque development, atherosclerotic nanoplaque formation and size were monitored by laser ellipsometry (patent EP 0 946 876). Lipoproteins, cytosolic SOD, oxLDL, and [cAMP] and [cGMP] were determined by established methods. Results: After 2-month medication, the decrease in nanoplaque formation amounted to 11.9 ± 2.5% (p < 0.01) and in nanoplaque size to 24.4 ± 8.1% (p < 0.02), after 5 years 25.0 ± 3.7% (p < 0.01) and 45.8 ± 9.5% (p < 0.01), respectively. A multiple correlation between nanoplaque reduction and the risk factors oxLDL/LDL, Lp(a) and cGMP yielded an estimate of their relative contribution to nanoplaque diminution (34.7%, 43.3%, 22.0%). In the 5 year follow-up examination using high-resolution CT, all arterial and 86.7% of the venous bypasses were open, whereby the increase in blood nucleotides seemed to have played a prominent role. Conclusion: Ginkgo may be used as complementary drug with potentially preventive character after coronary-artery bypass graft.

Aberrant expression of FcγRIIIA (CD16) contributes to the development of atherosclerosis

Previous studies have documented that Fc receptor III A of immunoglobulin G (FcγRIIIA, also named CD16) is involved in the development of coronary heart disease (CHD). However, the mechanism responsible for FcγRIIIA's in contribution to CHD development remains largely unclear. Herein, we investigated the possible role of FcγRIIIA in the development of atherosclerosis. Our results showed that the elevated level of FcγRIIIA on monocytes closely correlated to the adhesive efficiency of human umbilical vein endothelial cells (HUVECs) in vitro. Importantly, we also observed increased population of CD16+ monocytes and elevated CD16 level on monocytes in ApoE−/− mice with characterized atherosclerosis after feeding with high-fat diet for 10weeks. The enhancement of CD16 on monocytes closely correlated to increased content of MMP-9 in aorta and increased inflammatory cytokines in sera. In addition, similar to simvastatin, recombinant human M-CSF represented a robust inhibitory influence on plaque instability and inflammation. Taken together, these data established that FcγRIIIA (CD16)-mediated signaling orchestrated by interaction between monocytes and HUVECs, coupled with inflammatory cytokine stimulation and MMP activation, as a fundamental pathway linked to the development of atherosclerotic formation. Inhibition of FcγRIIIA or its signaling thus might represent a promising approach for the prevention and treatment of CHD.

Establishment of nasal tolerance to heat shock protein-60 alleviates atherosclerosis by inducing TGF-β-dependent regulatory T cells

Mounting evidence supports that a newly identified regulatory T cell (Treg), CD4(+)LAP(+) Treg, is associated with oral tolerance induction and following inhibition of atherosclerosis, but little is described about whether nasal tolerance to antigen likewise induces the novel Tregs production and the relevant antiatherosclerotic benefit. We investigated the effect of nasal administration of heat shock protein-60 (HSP60) on atherogenesis. HSP60 or phosphate buffer solution (PBS) was nasally administered to six-week-old male ApoE(-/-) mice. At the 10th week after the nasal administration, there was a significant decrease in atherosclerotic plaque areas of aortic roots in the HSP60-treated mice as compared with those in the PBS-treated mice. Atherosclerosis suppression was accompanied with a significant increase in CD4(+)LAP(+) and CD4(+)CD25(+)Foxp3(+) Tregs and a concurrently increased production of TGF-β in the HSP60-treated mice. The protective effect of HSP60 was offset by injection of anti-TGF-β antibody. It is concluded that nasal administration of HSP60 can inhibit atherosclerotic formation through immune tolerance which is established by Tregs depending on the induction of anti-inflammatory cytokine TGF-β. Immune tolerance induced by nasal administration of HSP60 may provide an alternative therapeutic method for atherosclerosis.

Therapeutic Modulation of Lipoprotein-associated Phospholipase A2 (Lp-PLA2)

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a calcium-independent phospholipase A2 that circulates in plasma in association with lipoprotein particles, whereas in atherosclerotic plaques it is co-localized with macrophages. Lp-PLA2 generates two proinflammatory mediators, lysophosphatidylcholine and oxidized nonesterified fatty acids, which play a role in the development of atherosclerotic lesions and formation of a necrotic core, leading to more vulnerable plaques. Epidemiologic studies demonstrate that increased circulating levels of Lp-PLA2 predict an increased risk of myocardial infarction, stroke and cardiovascular mortality. Furthermore, histologic examination of diseased human coronary arteries reveals intense presence of the enzyme in atherosclerotic plaques that are prone to rupture. These considerations suggest Lp-PLA2 as a promising therapeutic target in cardiovascular disease. Plasma levels of Lp-PLA2 are increased in various types of hyperlipidemias, while hypolipidemic drugs reduce plasma Lp-PLA2 activity and mass along with the improvement of plasma lipid profile. A selective inhibitor of Lp-PLA2 activity, darapladib, has been developed and studies in animal models and humans have shown that it effectively and safely reduces Lp-PLA2 activity in plasma and in atherosclerotic plaques. Furthermore, in animal models darapladib decreases plaque area and necrotic core area whereas in humans it prevents the expansion of necrotic core volume. Whether the results obtained from the use of darapladib in studies in vitro, as well as in preclinical and clinical studies would translate into benefits on cardiovascular event outcomes, awaits to be proved in 2 ongoing phase 3 trials.

Aberrant expression of Fcγ RIIIA contributes to development of atherosclerosis

PurposePrevious studies have shown that Fc receptor III A of immunoglobulin G (FcγRIIIA, also named CD16) was involved in the development of coronary heart disease (CHD). However, the mechanism of...

A Multiscale Model of Atherosclerotic Plaque Formation at Its Early Stage

A multiscale model of atherosclerotic plaque formation at its early stage has been developed in order to integrate the various phenomena leading to fatty streak formation. The different scales considered in this model are in both the spatial domain (from cellular to organism level) and the time domain (from seconds to months). The cellular level was considered by modeling the transport and chemical interactions of low-density lipoproteins (LDL) and other agents in a stenosed artery. This was linked to arterial thickening (organ level). Mean blood LDL level (organism level) was selected as one of the critical factors for atherosclerotic formation along with wall shear stress (WSS) exerted on the endothelium (the inner portion of the artery). It was observed that plaque location was dependent on WSS and that plaque size, number, and growth was dependent on mean blood LDL levels as well.

The inhibition of lipoprotein-associated phospholipase A2 exerts beneficial effects against atherosclerosis in LDLR-deficient mice

To investigate the effects of darapladib, a specific inhibitor of lipoprotein-associated phospholipase A2 (lp-PLA2), on inflammation and atherosclerotic formation in the low density lipoprotein receptor (LDLR)-deficient mice. Six-week-old LDLR-deficient mice were fed an atherogenic high-fat diet for 17 weeks and then randomly divided into two groups. One group was administered darapladib (50 mg·kg(-1)·d(-1); po) for 6 weeks. The other group was administered saline as a control. Serum lipid levels were measured using the corresponding kits, and three inflammatory markers--interleukin-6 (IL-6), C reactive protein (hs-CRP), and platelet activating factor (PAF)--were determined using ELISA. Atherosclerotic plaque areas were stained with Sudan IV, and inflammatory gene expression at the lesions was evaluated using quantitative real-time PCR. The body weight and serum lipid level between the two groups were similar at the end of the dietary period. The serum lp-PLA2 activity, hs-CRP and IL-6 levels, however, were significantly reduced in the darpladib group. The inhibition of lp-PLA2 did not alter the serum PAF level. Furthermore, the plaque area, from the aortic arch to the abdominal aorta, was significantly reduced in the darpladib group. Additionally, the expression of inflammatory genes monocyte chemotactic protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) was significantly reduced at the lesions in the darapladib group. Inhibition of lp-PLA2 by darapladib decreases the inflammatory burden and atherosclerotic plaque formation in LDLR-deficient mice, which may be a new strategy for the treatment of atherosclerosis.

Effects of Fufang Zhenzhu Tiaozhi Prescription (), A Chinese herbal preparation, on atherosclerosis in ApoE-/- mice and related mechanisms.

OBJECTIVE: The present study was designed to observe the effects and the possible mechanisms of Fufang Zhenzhu Tiaozhi Prescription (, FZT), a Chinese herbal preparation, on atherosclerosis in apolipoprotein E deficient (ApoE-/-) mice. METHODS: ApoE-/- mice were randomized to groups orally administrated without or with FZT (4.5 and 9 g crude drug/kg body weight, respectively). Atherosclerotic plaques, lipids profifiles in serum, aortic cholesterol content, serum indices of oxidative stress were measured, and mRNA expressions of scavenger receptors CD36 and scavenger receptor-A (SR-A) in aorta were analyzed. RESULTS: FZT dose-dependently suppressed the atherosclerotic plaques and reduced the cholesterol contents in aorta (P<0.05, P<0.01). In addition, FZT decreased the levels of total cholesterol and triglyceride in serum (P<0.05, P<0.01), inhibited the production of oxidized low density lipoprotein and malonaldehyde, and increased the superoxide dismutase activity in serum (P<0.05 or P<0.01). Furthermore, FZT down-regulated the mRNA expressions of CD36 and SR-A in the aorta (P<0.05, P<0.01). CONCLUSIONS: FZT reduced the atherosclerotic formation in ApoE-/- mice. The mechanisms might be related to the decrease of serum lipid level, the improvement of oxidative stress and the down-regulated expressions of scavenger receptors CD36 and SR-A, consequently reducing the foam cell formation, the hallmark of early atherosclerosis.

Vasculoprotective effects of rosiglitazone through modulating renin-angiotensin system in vivo and vitro

BackgroundThe peroxisome proliferator-activated receptor-γ (PPARγ) agonist rosiglitazone has been suggested to exert cardiovascular protection through the improvement of lipid metabolism, anti-inflammation, anti-proliferation etc. However, whether renin-angiotensin system (RAS) is involved in the vascular protective effects of PPARγ agonists is not fully understood. The present study aimed to investigate the effects of the renin-angiotensin system in vascular protection mediated by PPARγ agonists.ObjectiveTo investigate the actions of the renin-angiotensin system in vascular protection mediated by activation of PPARγ in vivo and in vitro.MethodsRats were fed a regular diet (n = 8), a cholesterol-rich diet plus methylthiouracil (80 mg/Kg/day, n = 10), a cholesterol-rich diet plus methylthiouracil and rosiglitazone (4 mg/kg/day, n = 10). The rosiglitazone treatment was started from one month after the start of cholesterol-rich diet plus methylthiouracil, and lasted five months. Cultured vascular smooth muscle cells (VSMCs) were pretreated with 1 μmol/L angiotensin II (ANG II) for 6 h and randomly divided into the control group; the ANG II group (1 μmol/L ANG II); the groups respectively treated with different concentration rosiglitazone (20, 30, 50) μmol/L for 12 h; the groups treated with 30 μmol/L rosiglitazone for (6, 12, 24) h. Morphology changes of the aortic tissues were observed by hematoxylin and eosin stain. The VSMC growth was detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) colorimetric assay. Angiotensin II and expression of angiotensin receptors were determined by radioimmunoassay, reverse transcription polymerase chain reaction (RT-PCR), western blot, and immunohistochemistry.ResultsAfter 6 months, lipid deposition, VSMC proliferation and migration toward intima were observed in aortic tissues in the rats on a cholesterol-rich diet plus methylthiouracil, while these pathological changes induced by the cholesterol-rich diet were significantly suppressed by rosiglitazone. In addition, VSMC proliferation induced by ANG II was markedly inhibited by rosiglitazone. Rosiglitazone markedly down-regulated expression of angiotensin type 1 receptor (AT1R) and up-regulated expression of angiotensin type 2 receptor (AT2R) in the aortic tissues and ANG II-treated VSMCs.ConclusionsThe present study demonstrated that PPARγ agonist rosiglitazone suppressed ANG II-induced VSMC proliferation in vitro and early atherosclerotic formation evoked by cholesterol-rich diet in vivo. These vasculoprotective effects of rosiglitazone were mediated at least partially by reduction in local tissue ANG II concentration, down-regulation of AT1R expression and up-regulation of AT2R expression both at the mRNA and protein levels.

LOX-1 mediates vascular lipid retention under hypertensive state

Hypertension is a powerful independent risk factor for atherosclerotic cardiovascular diseases; however, the precise molecular mechanisms whereby hypertension promotes atherosclerotic formation remain to be determined. The interaction between oxidized low-density lipoprotein (oxLDL) and its receptor lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) plays a critical role in atherogenesis. To clarify how hypertension promotes atherosclerosis, we investigated specific roles of LOX-1 in acceleration of lipid deposition under a hypertensive state. We employed a model of stroke-prone spontaneously hypertensive rats (SHR-SP) that exhibits acute lipid deposition in mesenteric artery induced by high fat and salt loading. These vascular lipid deposition lesions share similar characteristics with the initial lesions of human atherosclerosis. The enhanced LOX-1 expression in SHR-SP was associated with oxidized LDL deposited in vascular wall. Anti-LOX-1 neutralizing antibody dramatically suppressed the lipid deposition in vivo in SHR-SP. Vitamin E decreased serum oxLDL-like LOX-1 ligands, and suppressed the vascular lipid deposition. The vascular permeability, evaluated by the leakage of Evans blue, was markedly enhanced by pretreatment of oxLDL. The enhancement of vascular permeability induced by oxLDL was suppressed by anti-LOX-1 antibody. The enhanced expression and activation of LOX-1 mediated the enhancement of vascular permeability, which contributed to the vascular lipid accumulation under hypertensive states.

細胞外マトリックスと動脈硬化

Many kinds of extracellular matrixes (ECMs) are mainly produced by smooth muscle cells (SMC) in both normal arterial walls and atherosclerotic lesions. In particular, type I, III, IV, V, and VIII collagens and elastin are highly expressed in atherosclerotic lesions. The matrix metalloproteinases (MMPs) constitute multigene family enzymes and play a central role in the degradation of ECM components. The expression of MMPs is related to atherosclerotic formation. The MMPs produced by SMC and macrophages are MMP-1, 2, 3, 7, 9 and 12 in the arterial wall, and have their highest expression in atherosclerotic lesions. This review focuses on recent work on matrix metalloproteinases and extracellular matrixes in relation to atherosclerosis.

Propylthiouracil, independent of its antithyroid effect, promotes vascular smooth muscle cells differentiation via PTEN induction

Propylthiouracil (PTU), independent of its antithyroid effect, is recently found to have an antiatherosclerotic effect. The aim of this study is to determine the impact of PTU on phenotypic modulation of vascular smooth muscle cells (VSMCs), as phenotypic modulation may contribute to the growth of atherosclerotic lesions and neointimal formation after arterial injury. Propylthiouracil reduced neointimal formation in balloon-injured rat carotid arteries. In vitro, PTU may convert VSMCs from a serum-induced dedifferentiation state to a differentiated state, as indicated by a spindle-shaped morphology and an increase in the expression of SMC differentiation marker contractile proteins, including calponin and smooth muscle (SM)-myosin heavy chain (SM-MHC). Transient transfection studies in VSMCs demonstrated that PTU induced the activity of SMC marker genes (calponin and SM-MHC) promoters, indicating that PTU up-regulates these genes expression predominantly at the transcriptional level. Furthermore, PTU enhanced the expression of PTEN and inhibition of PTEN by siRNA knockdown blocked PTU-induced activation of contractile proteins expression and promoter activity. In the rat carotid injury model, PTU reversed the down-regulation of contractile proteins and up-regulated PTEN in the neointima induced by balloon injury. Propylthiouracil promotes VSMC differentiation, at lest in part, via induction of the PTEN-mediated pathway. These findings suggest a possible mechanism by which PTU may contribute to its beneficial effects on atherogenesis and neointimal formation after arterial injury.

Inhibitory effect of N-acetylcysteine upon atherosclerotic processes in rabbit carotid

To discuss the effect of N-acetylcysteine (NAC) upon matrix metalloproteinases (MMP) in the atherosclerotic processes in rabbit carotid. The atherosclerotic models were generated in vitro by injuring rabbit internal carotid with arterial canal balloon. These rabbits were divided into 3 groups (15 mg/kg NAC, 30 mg/kg NAC and control group) and treated for 8 weeks. HE staining and immunohistochemistry were used to observe the plaque formation and the distribution of MMPs and ox-LDL. ELISA was used to detect the level of ox-LDL. And the protein levels of MMP-2 and MMP-9 in rabbit venous blood were detected by SDS PAGE zymography. The mRNA level of MMP-2 and MMP-9 were measured by RT-PCR and electrophoresis. As compared with the control group, NAC (15 mg/kg) group had a reduction of neointima of arterial lumen [(1.79 +/- 0.24) vs (2.78 +/- 0.17) mm2]. A decrease of endothelial thickness [(0.16 +/- 0.01) vs (0.24 +/- 0.02) mm2] and an increase of vascular cavity transverse [(0.58 +/- 0.10) vs (0.33 +/- 0.1) mm2] (P < 0.05) were observed. At week 8, the oxLDL levels decreased by 16% in NAC (30 mg/kg) group [(30.5 +/- 1.2) vs (36.2 +/- 1.8) mmol/L] (P < 0.01). Serum levels of pro-MMP-2, MMP-2 and pro-MMP-9 decreased markedly [INT/mm2: (311 +/- 19, 208 +/- 8, 283 +/- 7 vs 619 +/- 17, 574 +/- 8, 564 +/- 10) respectively, P < 0.01] in NAC (30 mg/kg) group. The levels of mRNA expression of MMP-2 and MMP-9 were (2.4 +/- 0.4, 2.8 +/- 0.2) vs (3.4 +/- 0.3, 3.7 +/- 0.5) respectively (P < 0.05). NAC inhibits the atherosclerotic formation, suppresses the levels of ox-LDL, MMP-9 and MMP-2 and downgrades the expression of matrix metalloproteinase mRNA.

Stent thrombosis is not always stent thrombosis: De novo atherosclerosis in a stented coronary segment

We discuss a case of late thrombosis, 9 years after implantation of overlapping bare metal stents in a circumflex artery. The patient presented with an acute ST segment elevation infero-lateral myocardial infarction. The coronary angiogram revealed a sub-occlusive thrombus within the boundaries of the stents. Aspiration of the material was performed and pathological analysis showed, together with fibrin thrombus and platelet aggregates, fragments of an atherosclerotic plaque (parts of necrotic core with cholesterol clefts and inflammatory cells such as macrophages) including iron deposition, suggestive for plaque rupture. We conclude that this event occurred because of de novo atherosclerotic formation of a vulnerable, rupture-prone plaque within the boundaries of the stents.

Abstract 1732: Deletion of Fc Receptor Ameliorates Progression of Atherosclerotic Lesions in LDL Receptor Knockout Mice: Protective Role against Vascular Inflammation and Oxidative Stress

Background : Vascular endothelial dysfunction through the production of reactive oxygen species (ROS) plays an important role in the initiation and progression of atherosclerosis. Immunoglobulin Fc receptor (FcR) involves the activation of immune and inflammatory reaction, however, the role of FcR in endothelial function, ROS production, and atherogenesis, has not clearly elucidated. To examine the hypothesis that FcR deletion blunts the progression of atherosclerotic lesions via improvements of superoxide production and endothelial dysfunction, we generated FcR/LDL receptor double-knockout (DKO) mice. Methods : Mice (8 weeks) with LDL receptor knockout (LDLR-KO) and DKO were fed a high cholesterol diet for 10 weeks. We examined the endothelium-dependent relaxation of isolated thoracic aorta, superoxide production by dihydroethidium-derived fluorescence (DHE) staining before and after high cholesterol feeding. We also assessed atherosclerotic lesions by Oil Red O-staining, macrophage infiltration, and p22phox expression by immnohistochemical analysis. Results : Vascular endothelial-dependent relaxation induced by high cholesterol diet was significantly higher in DKO mice than in LDLR-KO mice (−53 ± 7% vs −22 ± 9, p &lt; 0.05). Superoxide production was significantly lower in DKO mice than in LDLR-KO mice (13.6 ± 10 vs 38.8 ± 20 ×10 3 μ m 2 p &lt; 0.05). The expression of p22phox in DKO mice was significantly lower than in LDLR-KO mice (90 ± 19 vs 141 ± 42 × 10 3 μm 2 p &lt; 0.05). The area of macrophage infiltration of the vascular wall was significantly lower in DKO mice than LDLR-KO mice (34 ± 5 vs 59 ± 17 × 10 3 μ m 2 p &lt; 0.05). The Oil -Red O staining showed the significant reduction of atherosclerotic lesions in DKO mice than in LDLR-KO mice (73 ± 24 vs 133 ± 31 × 10 4 μ m 2 p &lt; 0.005). Conclusion : Deletion of FcR attenuated the production of ROS, vascular inflammation, and endothelial dysfunction, resulting in prevention of atherosclerotic formation in LDLR-KO mice. These data suggested that FcR might be involved in atherosclerotic process through not only vascular inflammation, but also oxidative stress in vasculature.

Effect of Hibiscus anthocyanins‐rich extract induces apoptosis of proliferating smooth muscle cell via activation of P38 MAPK and p53 pathway

Hibiscus sabdariffa L. (Malvaceae), an attractive plant believed to be native to Africa, is cultivated in Sudan and in eastern Taiwan. It has been reported to contain a number of protocatechuic acid and anthocyanins. In vitro experimental studies have shown that anthocyanins administration of the extract produces anti-inflammation and chemoprevention effects. In spite of the wide use of Hibiscus sabdariffa L. in folk medicine for treating various diseases, our previous study indicated a potency of Hibiscus sabdariffa extract (HSE) in anti-atherosclerosis. The mechanisms of anthocyanins administration of the extract produce from Hibiscus sabdariffa L. to attenuate atherosclerosis were not clarified. In this study, we found that Hibiscus anthocyanins (HAs) could inhibit the serum-stimulated proliferation of smooth muscle cell (SMC) and result in cell apoptosis. The HAs inducing cell apoptosis was dose dependent. We further used SB203580 (p38 inhibitor) to block cellular apoptosis and evaluate its effect on the HAs-inducing SMC death via some apoptosis criteria including DNA fragmentation and flow cytometry. We suggested that the mechanisms of the inhibitory effect of HAs on atherosclerosis could be via inhibiting the proliferation of SMC. HAs induces apoptosis via (i) activating p38 MAP kinase that subsequently phosphorylates target protein c-Jun and transduces the signal to further activate the apoptotic protein cascades that contain Fas-mediated signaling (Fas/caspase-8 signaling module) and (ii) activating p53 and inducing bax expression. As an outcome of the events, cytochrome c releases from the mitochondria, leading to cell apoptosis. In these experiments, HAs showed strong potential to induce SMC cell apoptosis via p38 and p53 pathway. In consequence, the rate of atherosclerotic formation is slowed down, and the progress is suppressed.

Pharmacology of thienopyridines: rationale for dual pathway inhibition

Atherothrombotic disease is the result of atherosclerosis progression, and its clinical manifestations, mostly secondary to atherosclerotic plaque disruption and subsequent thrombus formation. At the site of vascular lesions, platelets adhere to the exposed matrix proteins, prompting platelet activation, resulting in the secretion of multiple platelet agonists, mostly modulated by intracellular calcium release. Among them, ADP, thromboxane A2, thrombin, and others play a critical role in maintaining a ‘pro-platelet-activating’ environment. Aspirin has been considered the gold standard of antithrombotic therapy. Its antiplatelet activity is achieved mainly by inhibiting arachidonic acid pathway (blocking thromboxane A2 release from platelets). ADP binds to platelet P2Y12 receptor, although this receptor is important in platelet aggregation induced by other agonists. Thienopyridines (ticlopidine and clopidogrel) exert their antiplatelet activity by binding to the P2Y12 receptor, irreversibly modifying it. Oral clopidogrel loading dose of 300–600 mg clopidogrel produces significant inhibition of ADP-induced platelet aggregation 2 hours after administration, which becomes maximal after 6 hours. Both aspirin and clopidogrel are ‘selective platelet-receptor’ inhibitors, and therefore are weak and safe antiplatelet agents. The co-administration aspirin-clopidogrel results in enhancement of platelet inhibition, since the act via different platelet receptors. Current research is focused in reversible or more potent ADP antagonists.

Deficiency of inducible NO synthase reduces advanced but not early atherosclerosis in apolipoprotein E-deficient mice

The inducible nitric oxide synthase (iNOS) is abundantly expressed by smooth muscle cells and macrophages in atherosclerotic lesions. Apolipoprotein E-deficient (apoE −/−) mice develop early and advanced atherosclerotic lesions. The role of iNOS in both early and advanced atherosclerotic formation was determined in apoE −/− mice. Mice were fed chow or a Western diet containing 42% fat, 0.15% cholesterol, and 19.5% casein. At 12 weeks of age on chow diet, iNOS −/−/apoE −/− mice developed comparable sizes of early atherosclerotic lesions in the aortic root as did iNOS +/+/apoE −/− mice (30,993 ± 4746 vs. 26,648 ± 6815 μm 2/section; P = 0.608). After being fed the Western diet for 12 weeks, iNOS −/−/apoE −/− mice developed significantly smaller advanced lesions than iNOS +/+/apoE −/− mice (458,734 ± 14,942 vs. 519,570 ± 22,098 μm 2/section; P = 0.029). This reduction in lesion formation could not be explained by differences in plasma lipid levels. To examine whether iNOS contributed to LDL oxidation, smooth muscle cells were isolated from the aorta, activated with TNF-α, and then incubated with native LDL in the absence or presence of N-Ω-nitro- l-arginine methyl ester (L-NAME), a specific NOS inhibitor. L-NAME significantly inhibited LDL oxidation by smooth muscle cells from iNOS +/+/apoE −/− mice ( P = 0.048), but it had no effect on LDL oxidation by cells from iNOS −/−/apoE −/− mice. iNOS −/−/apoE −/− mice had a significantly lower plasma lipoperoxide level on the Western diet (2.74 ± 0.23 vs. 3.89 ± 0.41 μM MDA; P = 0.021) but not on chow diet (1.02 ± 0.07 vs. 1.51 ± 0.29 μM MDA; P = 0.11). Thus, the absence of iNOS-mediated LDL oxidation may contribute to the reduction in advanced lesion formation of iNOS −/−/apoE −/− mice.

The Role of Oral Antiplatelet Agents in Atherothrombotic Disease

Atherothrombosis involves the mutually interactive dual mechanistic processes of atherosclerotic plaque progression and thrombus formation. In the setting of acute plaque rupture, resultant thrombus formation precipitates acute ischemic events such as acute coronary syndromes (ACS), stroke, and transient ischemic attack. Peripheral arterial disease is also a manifestation of atherothrombotic disease, and occurs both acutely and as a result of underlying disease progression. Atherothrombotic disease is highly prevalent and imposes a substantial burden on the community. For example, coronary artery disease was the single greatest cause of mortality among men and women in the US and accounted for an estimated US dollars 142.1 billion in health costs in 2005. Activated platelets are the prime mediators of arterial thrombus formation. This review discusses the evidence supporting the use of oral antiplatelet agents with other risk prevention strategies in the long-term secondary prevention of atherothrombotic disease. The most widely used oral antiplatelet agent is aspirin (acetylsalicylic acid), and both aspirin and clopidogrel have proven roles in the management of atherothrombotic disease. Clopidogrel should also be used in combination with aspirin in patients with non-ST-segment elevation ACS and those undergoing percutaneous coronary intervention. Recent data suggest that clopidogrel may have a significant role, with or without fibrinolytic therapy, in the immediate management of ST-segment elevation ACS.

Lipoprotein(a) immune complexes induce cholesteryl ester accumulation in human macrophages

目的 探讨氧化、天然脂蛋白(a)[Lp(a)]循环免疫复合物(IC)致动脉粥样硬化作用.方法采用人源的氧化、天然Lp(a)与异源的抗载脂蛋白B(apoB)结合制备IC,观察不同浓度的Lp(a)-IC对小鼠腹腔巨噬细胞胆固醇酯的蓄积和泡沫细胞形成作用.结果氧化、天然Lp(a)-IC均引起巨噬细胞内胆固醇酯大量堆积,其效果强于Ox-Lp(a) (P<0.001),且随着剂量的增加而升高,并转化为泡沫细胞;而天然Lp(a)、抗apoB处理的巨噬细胞内未见胆固醇酯的堆积.结论 Lp(a)-IC导致巨噬细胞转化为泡沫细胞,参与动脉粥样硬化形成。