Remnant-like particles accelerate endothelial progenitor cells senescence and induce cellular dysfunction via an oxidative mechanism.
ABSTRACT Remnant-like particles (RLPs) are closely associated with coronary heart disease and can induce endothelial dysfunction through oxidative mechanisms. Many risk factors accelerate the onset of endothelial progenitor cells (EPCs) senescence via increased oxidative stress. In this study, we investigated the effect of RLPs on EPCs senescence and function. RLPs were isolated from postprandial plasma of hypertriglyceridemic patients by use of the immunoaffinity gel mixture of anti-apoA-1 and anti-apoB-100 monoclonal antibodies. Our results show that EPCs became senescent as determined by senescence-associated acidic beta-galactosidase (SA-beta-Gal) staining after ex vivo cultivation without any stimulation. Co-incubation with RLPs accelerated the increase in SA-beta-Gal-positive EPCs. The acceleration of RLPs-induced EPCs senescence occurred dose-dependently with a maximal effect when EPCs were treated with RLPs at 0.10 mg cholesterol/mL (P<0.01). Moreover, RLPs decreased adhesion, migration and proliferation capacities of EPCs as assessed by adherence to fibronectin, modified Boyden chamber technique and MTT assay (P<0.01), respectively. RLPs increased nitrotyrosine staining in EPCs. However, RLPs-induced EPCs senescence and dysfunction were significantly inhibited by pre-treatment of superoxide dismutase (50 U/mL) (P<0.05). Our results provide evidence that RLPs accelerate the onset of EPC senescence via increased oxidative stress, accompanying with the impairment of adhesion, migration and proliferation capacities.
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ABSTRACT: Our previous studies showed that homocysteine (Hcy) reduces endothelial progenitor cell (EPC) numbers and impairs functional activity. However, the mechanisms by which Hcy reduces EPCs numbers and activity remain to be determined. Recent studies have demonstrated that reduced EPCs numbers and activity was associated with EPCs senescence which involved telomerase activity. Therefore, we investigated whether Hcy accelerates the onset of EPCs senescence through telomerase inactivation, leading to cellular dysfunction. EPCs were isolated from peripheral blood and characterized. After ex vivo cultivation, EPCs became senescent as determined by acidic beta-galactosidase staining. Hcy dose-dependently accelerated the onset of EPCs senescence in culture. Moreover, Hcy decreased proliferation of EPCs as assessed by BrdU incorporation assay and colony-forming capacity. To get further insights into the underlying mechanisms of these effects induced by Hcy, we measured telomerase activity and determined the phosphorylation of Akt by using western blot. Hcy significantly diminished telomerase activity and Akt phosphorylation. Taken together, the results of the present study demonstrated that Hcy accelerated the onset of EPCs senescence, leading to cellular dysfunction. The effect of Hcy might be dependent on telomerase inactivation, and Akt dephosphorylation also appeared to play a major role. In addition, atorvastatin had a preventative effect against Hcy-induced EPCs senescence.Journal of Molecular and Cellular Cardiology 06/2006; 40(5):648-52. · 5.15 Impact Factor
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ABSTRACT: Oxidized chylomicrons may be a metabolic factor involved in the injury of the arterial wall and may constitute a potential link between postprandial lipemia and atherogenesis. It was of interest to study the influence of dietary fatty acid composition on the oxidizability and subsequent cytotoxicity of chylomicrons on cultured cells. Human chylomicrons were obtained from healthy volunteers 3 h after ingestion of a triglyceride-rich meal containing mainly either polyunsaturated fatty acids (soya oil) or monounsaturated fatty acids (olive oil) or saturated fatty acids (partly hydrogenated palm oil). Polyunsaturated fatty acid (PUFA)-rich chylomicrons exhibited a high oxidizability, whereas chylomicrons enriched with monounsaturated or saturated fatty acids were relatively resistant to oxidation. The cytotoxicity of various types of chylomicrons submitted to oxidation has been tested comparatively on cultured human monocytic U937 cells and endothelial cells. Chylomicrons enriched with saturated and monounsaturated fatty acids were not or only slightly cytotoxic to cultured cells, whereas PUFA-rich chylomicrons (highly susceptible to oxidation) were highly cytotoxic. The influence of cholesterol on the oxidizability and subsequent cytotoxicity of PUFA-rich chylomicrons has been investigated by using comparatively a soya diet supplemented or not with cholesterol. PUFA-rich cholesterol-rich chylomicrons were slightly more oxidizable and more cytotoxic than PUFA-rich (cholesterol-poor) chylomicrons, thus suggesting that the cytotoxicity of PUFA-rich chylomicrons may be due to oxidation derivatives of PUFA (for the major part) and to oxysterols (for a minor part). Furthermore, the cytotoxic effects of oxidized PUFA-rich chylomicrons and of mildly oxidized LDL were in similar range (even higher for PUFA-rich chylomicrons when expressed per lipoprotein particle), thus suggesting that oxidized PUFA-rich chylomicrons may play a nonnegligible role in cytotoxic events occurring during atherogenesis.(ABSTRACT TRUNCATED AT 250 WORDS)Free Radical Biology and Medicine 12/1995; 19(5):599-607. · 5.27 Impact Factor
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ABSTRACT: Recent studies have demonstrated that elevated levels of cholesterol in the form of remnant-like particles (RLP-C) induce deterioration of endothelial function during the fasting state, but it is not known whether postprandial RLP-C elevation has the same effect. The objective of this study was to assess the effect of postprandial RLP-C elevation on endothelial function in 24 fasting normolipidemic subjects. Flow-mediated dilatation (FMD) during reactive hyperemia in the brachial artery was investigated. Serum lipids and lipoproteins during fasting and 4h after regular fat-loading were measured. Subjects were divided into 2 groups: the high responders (postprandial RLP-C level >7.5mg/dl, n=8) and the normal responders (postprandial RLP-C level < or =7.5mg/dl, n=16). Significant increases in the level of both triglycerides and RLP-C were observed in the high responders. Basal FMD in the high responders (4.3+/-3.0%) was significantly lower than that in the normal responders (8.3+/-2.4%) (p<0.01), but FMD after the fat-loading in both groups did not change significantly. The change in RLP-C levels during the fat-loading test correlated significantly with basal FMD (r=-0.588, p<0.01). Multiple regression analysis showed a significant correlation between basal FMD and the change in RLP-C levels (r=-0.488, p<0.02). The results of this study suggest that postprandial RLP-C elevation could be associated with atherosclerotic progression even in normolipidemic subjects.Circulation Journal 03/2002; 66(2):127-32. · 3.58 Impact Factor