T cells and cytokines in atherogenesis.
ABSTRACT Recent findings suggest that inflammation plays a key role in atherosclerosis from the earliest stage of lesion initiation, to the ultimate complication of thrombosis. In patients who died because of acute coronary syndromes (ACS), coronary atherosclerotic plaques are characterized by the presence of macrophages, and to a lesser extent T-lymphocytes, at the immediate site of either plaque rupture or superficial erosion. The rupture-related inflammatory cells are activated, indicating ongoing inflammation. ACS patients are also characterized by activated circulating lymphocytes, monocytes and neutrophils, and by increased concentrations of proinflammatory cytokines and of the highly sensitive acute phase reactant C-reactive protein. Interestingly, an unusual subset of T cells, CD4+ CD28null T cells, involved in vascular complication of rheumatoid arthritis because of their functional profile predisposing for vascular injury, are expanded in the peripheral blood and infiltrate the coronary lesions of ACS patients. The presence of activated T lymphocytes implies antigenic stimulation, but the nature of such antigen(s) remains to be investigated. Several autoantigens expressed in the atherosclerotic plaque, including oxidized LDL and heat shock proteins, and infectious agents are able to elicit an immune response. The inflammatory component is not localized to the 'culprit' plaque, but it is diffused to the entire coronary vascular bed, and involves also the myocardium.
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ABSTRACT: Risk factors for atherosclerosis may contribute to chronic low-grade inflammation. A highly cytotoxic and inflammatory CD4(+) cell subset (CD4(+)CD28(null) cells) has been associated with inflammatory diseases, including acute coronary syndromes (ACS). The aim of this study was to quantify and characterize CD4(+)CD28(null) cells in individuals with risk factors for atherosclerosis and patients with coronary artery disease (CAD). In order to achieve this goal, peripheral blood mononuclear cells (PBMCs) from individuals with risk factors for atherosclerosis and patients with CAD were analyzed using flow cytometry to detect cytotoxic molecules and evaluate the expression of homing receptors and inflammatory cytokines in CD4(+) cell subsets. The cells were evaluated ex vivo and after stimulation in culture. We found no differences in the proportions of CD4(+)CD28(null) cells among the groups. Compared with the CD4(+)CD28(+) population, the ex vivo CD4(+)CD28(null) subset from all groups expressed higher levels of granzymes A and B, perforin, granulysin and interferon-γ (IFN-γ). Individuals with risk factors and patients with ACS showed the highest levels of cytotoxic molecules. After stimulation, tumor necrosis factor-α (TNF-α) expression in the CD4(+)CD28(null) subset from these groups increased more than in the other groups. Stimulation with LPS decreased the expression of cytotoxic molecules by CD4(+)CD28(null) cells in all groups. In conclusion, our results show that risk factors for atherosclerosis may alter the CD4(+)CD28(null) cells phenotype, increasing their cytotoxic potential. Our findings also suggest that CD4(+)CD28(null) cells may participate in the early phases of atherosclerosis.Cellular Immunology 01/2013; 281(1):11-19. · 1.87 Impact Factor
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ABSTRACT: The present study investigated the effect and possible mechanisms of α-lipoic acid (LA) in preventing endothelial cell injury induced by oxidized low-density lipoprotein (oxLDL). A model of human umbilical vein endothelial cell (HUVEC) injury was established by incubating the HUVECs with 200 μg/ml oxLDL. HUVECs were pre-treated with 0.1, 0.2 or 0.5 mmol/l of LA in the presence of oxLDL for 24 h. Apoptosis and cellular surface ceramide content were investigated separately by flow cytometry and by LC-MS/MS. LOX-1, Bcl-2 and CRP protein expression levels were evaluated by western blotting. LOX-1 mRNA expression was evaluated by RT-PCR assay. The results showed that oxLDL induced cytotoxicity in both concentration-dependent and time-dependent manners. LA boosted the cell survival rate and significantly reduced the content of MDA and lactate dehydrogenase (LDH) leakage. Apoptotic rates were significantly reduced by the addition of LA compared to oxLDL group. LA might also have inhibited ceramide generation induced by oxLDL in a dose-dependent manner. Furthermore, LA down-regulated LOX-1 protein and mRNA expression and up-regulated Bcl-2 protein expression levels in a dose-dependent manner. Expression of CRP protein was weak and undetectable. These results suggested that LA exhibited cytoprotective effects against oxLDL by decreasing apoptotic rates and decreasing cellular surface ceramide content, two effects that are related to decreased LOX-1 expression, and also by stimulating the expression of Bcl-2 protein. The cytoprotective effects are not thought to be due to inhibited C-reactive protein (CRP) protein expression in HUVECs.Pharmacological reports: PR 09/2011; 63(5):1180-8. · 2.17 Impact Factor
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ABSTRACT: Antrodia salmonea (AS) is known as a traditional Chinese medicine, but very few biological activities have been reported. The present study was aimed to investigate the anti-angiogenic and anti-atherosclerotic potential of the fermented culture broth of AS against tumor necrosis factor-α (TNF-α)-stimulated human endothelial (EA.hy 926) cells. The non-cytotoxic concentrations of AS significantly inhibited TNF-α-induced migration/invasion and capillary-like tube formation in EA.hy 926 cells. Furthermore, AS suppressed TNF-α-induced activity and expression of matrix metalloproteinase-9 (MMP-9), and cell-surface expression of intercellular adhesion molecule-1 (ICAM-1), which was associated with abridged adhesion of U937 leukocytes to endothelial cells. Moreover, AS significantly down-regulated TNF-α-induced nuclear translocation and transcriptional activation of nuclear factor κB (NF-κB) followed by suppression of I-κB degradation and phosphorylation of I-κB kinase-α (IKKα). Notably, the protective effect of AS was directly correlated with the increased expression of hemeoxygenase-1 (HO-1) and γ-glutamylcysteine synthetase (γ-GCLC), which was reasoned by nuclear translocation and transactivation of NF-E2 related factor-2 (Nrf2)/antioxidant response element (ARE). Furthermore, HO-1 knockdown by HO-1-specific shRNA diminished the protective effects of AS on TNF-α-stimulated invasion, tube formation, and U937 adhesion in EA.hy 926 cells. Taken together, these results suggest that Antrodia salmonea may be useful for the prevention of angiogenesis and atherosclerosis.Journal of ethnopharmacology 11/2013; · 2.32 Impact Factor