PubMed · 7704776
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P B Duell, D R Illingworth. 1994. Hyperlipidemia.. https://pubmed.ncbi.nlm.nih.gov/7704776/
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Fibrinogen has been recognised in recent years as an independent risk factor in athero/thrombogenesis. However, the mechanism by which elevated fibrinogen translates into higher incidence of atherosclerosis is not known. One possible mechanism may be through the modification of fibrin. While it is already known that fibrin network is altered in disease states like peripheral vascular disease, diabetes, hypercholesterolaemia and myocardial infarction, the influence of altered fibrin network structure on growth and function of endothelial cells (EC) and fibroblasts (FB) requires investigation. Fibrin network structure in plasma clots was modified by changing pH and characterised using established biophysical methods. PGI(2), von Willebrand Factor (vWF), t-PA and PAI-1 were measured to evaluate changes in cell function induced by modified fibrin structure. In general, networks composed of thin fibres induced growth over their entire layer. Networks composed of thick fibres and open matrix promoted infiltration of cells into gel matrix and growth of macrovascular structures. Furthermore, thin fibres promoted a more prothrombotic environment as observed from changes in cell biochemical function. Fibrin, whilst initially acting as a scaffolding for cellular and biochemical processes, may also alter cell function and determine the progress of atherosclerosis.
BACKGROUND: Epidemiological studies and animal experiments have provided evidence supporting the role of lipid peroxidation in atherogenesis and cardiovascular diseases. Direct evidence linking lipid oxidation to atherosclerotic progression in humans, however, has been lacking. We investigated the association of lipid oxidation products with the progression of early carotid atherosclerosis in hypercholesterolemic men from eastern Finland. METHODS AND RESULTS: Twenty subjects with a fast progression and 20 with no progression of carotid atherosclerosis in 3 years were selected from > 400 participants in the Kuopio Atherosclerosis Prevention Study. Progression of carotid atherosclerosis was assessed by high-resolution B-mode ultrasonography. Serum 7 beta-hydroxycholesterol, a major oxidation product of cholesterol in membranes and lipoproteins, and seven other cholesterol oxidation products were measured by isotope dilution-mass spectrometry, lipid hydroperoxides in LDL fluorometrically as thiobarbituric acid-reactive substances (TBARS) and oxidation susceptibility of LDL and VLDL kinetically. High concentrations of serum 7 beta-hydroxycholesterol (beta = 47, P = .0005), cigarette smoking (beta = .35, P = .0167), and LDL TBARS (beta = .23, P = .0862) and an increased oxidation susceptibility of VLDL + LDL (beta = .22 P = .1114) were the strongest predictors of a 3-year increase in carotid wall thickness of more than 30 variables tested in step-up least-squares regression models. A 10-variable model explained 60% of the atherosclerotic progression. In a multivariate logistic model, the risk of experiencing a fast progression increased by 80% (P = .013) per unit (microgram/L) of 7 beta-hydroxycholesterol. CONCLUSIONS: The findings of this study provide further evidence to support an association between lipid oxidation and atherogenesis in humans.
Although clinical and experimental studies have supported a role of calcium in atherogenesis, the nature of this relationship has not been determined. The following investigation was performed to examine the effect of transmembrane calcium flux on the oxidative modification of low-density lipoprotein (LDL) by arterial smooth muscle cells (SMC). Confluent SMC were incubated in basal medium alone or in medium containing either nifedipine (0.25 microM), a calcium channel blocker, or dantrolene (10 microM), a blocker of calcium release from the endoplasmic reticulum. Cells were then suspended in medium with either physiologic (1.25 mM) or supraphysiologic (2.5 mM) calcium concentrations ([Ca2+]e) and were exposed to oxidized LDL (20 micrograms/protein/ml; 4.96 +/- 0.76 nmole malondialdehyde/mg LDL protein). Changes in cytosolic calcium ([Ca2+]i) were measured by spectrofluorometric analysis using a Fura 2-AM indicator. In similar studies, the cellular oxidation of native LDL was determined by fluorometric measurement of thiobarbituric acid-reactive substances in the media. Nifedipine and, to a lesser extent, dantrolene lowered steady-state [Ca2+]i at supraphysiologic [Ca2+]e (2.5 mM; P < 0.0002). Exposure of SMC to Ox-LDL increased [Ca2+]i (P < 10(7), which was further augmented by increasing [Ca2+]e (P < 10(-7). Nifedipine significantly reduced the calcium response to Ox-LDL proportionate to [Ca2+]e (P < 0.0002). A similar reduction in [Ca2+]i vs control was seen with dantrolene, but was independent of [Ca2+]e. TBARS assays revealed a significantly greater degree of cellular oxidation of native LDL following preincubation of SMC with Ox-LDL (P < 10(8). This effect was markedly inhibited by both nifedipine (P < 10(-8) and dantrolene (P < 10(-8), which showed some degree of synergism. These results indicate that the increase in cytosolic calcium in SMC exposed to Ox-LDL may occur through both membrane channels and reticular release. Inhibition of transmembrane calcium flux severely limits the cellular oxidation of low-density lipoprotein. These alternate means of calcium signal generation may allow a more varied response of the SMC to atherogenic stimuli and provide an opportunity for specific therapeutic intervention.