PubMed · 10475895
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G Krishnaswamy, D S Chi, J Kelley. 1999-09-07. Vulnerable plaque.. https://doi.org/10.7326/0003-4819-131-5-199909070-00015
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Oxidative modification of human low-density lipoprotein (LDL) renders it atherogenic. Previous studies demonstrated that plasma thiols promote oxidation of LDL by free ferric iron (Fe3+). The current study investigated effects of plasma thiols on oxidation of LDL by hemin, a physiological Fe3+-protoporphyrin IX complex thought to be capable of initiating LDL oxidation in vivo. In contrast to free Fe3+ which is incapable of oxidizing LDL in the absence of an exogenous reductant, hemin readily promoted LDL oxidation. During incubation of LDL (0.2 mg of protein/ml) with hemin (10 microM) at 37 degrees C for 6 h, thiobarbituric acid-reactive substances (TBARS), a marker of lipid oxidation, increased from 0.3 (+/-0.1) nmol/mg of LDL protein to a maximal concentration of 45.8 (+/-5.2) nmol/mg of LDL protein. Under the same experimental conditions, lipid-conjugated dienes, another marker of lipid oxidation, increased from non-detectable to near-maximal levels of 78-187 nmol/mg of LDL protein, and lipoprotein polyunsaturated fatty acyl-containing cholesteryl ester content decreased to 15-36% of that present in native (i.e. unoxidized) LDL. Continued incubation of LDL with hemin for up to 24 h resulted in no further significant alterations in lipoprotein levels of TBARS, lipid-conjugated dienes, and cholesteryl esters. In addition to these chemical modifications indicative of lipoprotein oxidation, agarose gel electrophoretic analysis indicated that exposure of LDL to hemin resulted in conversion of the lipoprotein to an atherogenic form as evidenced by its increased anodic electrophoretic mobility. Addition of physiological concentrations of plasma thiols (either cysteine, homocysteine or reduced glutathione; 1-100 microM, each) inhibited hemin-mediated oxidation of LDL. Thus, whereas the maximal TBARS concentration was achieved following 6 h of incubation of LDL with hemin alone, addition of thiol extended the time required to attain maximal TBARS concentration to > or = 12 h. Similar antioxidant effects of thiols on formation of lipid-conjugated dienes, loss of cholesteryl esters, and lipoprotein anodic electrophoretic mobility were also observed. However, all thiols were not equally effective at inhibiting hemin-dependent LDL oxidation. Thus, whereas reduced glutathione was most effective at inhibiting hemin-dependent LDL oxidation, an intermediate effect was observed for homocysteine, and cysteine was least effective. The inhibition of hemin-mediated LDL oxidation by plasma thiols reported here confirms a previous observation that, under certain conditions, thiols can function as antioxidants, but contrasts with the previously documented pro-oxidant effect of the same thiols on oxidation of LDL by free Fe3+. These contrasting effects of plasma thiols on hemin- and free Fe3+-mediated LDL oxidation indicate that, in vivo, the ability of thiols to function as either anti- or pro-oxidants during LDL oxidation may, at least in part, be determined by the type of oxidant stress to which the lipoprotein is exposed.
BACKGROUND: Observational data strongly suggest an association between Chlamydia pneumoniae and atherosclerotic cardiovascular disease. However, few studies have mechanistically linked C. pneumoniae to vascular remodeling. The purpose of the present study was to examine the mechanistic relationship between C. pneumoniae and human vascular smooth muscle cell (VSMC) physiology. We sought to determine the influence of human VSMC infection by C. pneumoniae on (1) VSMC proliferation and (2) activation of the proinflammatory and proliferative transcription factors nuclear factor kappaB (NF-kappaB) and activator protein 1 (AP-1). MATERIALS AND METHODS: C. pneumoniae was grown and isolated from Hep 2 cells. Human aortic VSMCs were inoculated with C. pneumoniae in the presence and absence of the azalide antibiotic azithromycin. Cell proliferation was assayed by direct cell counting 48 h following infection. Two hours following infection, nuclear extracts were isolated, and activation of both NF-kappaB and AP-1 was assessed by electrophoretic mobility shift assay. RESULTS: Compared with control, C. pneumoniae infection stimulated VSMC proliferation (P < 0.05) and induced both NF-kappaB and AP-1 DNA binding activity. These effects were eliminated by concurrent treatment with azithromycin. CONCLUSIONS: VSMC infection with C. pneumoniae activates proliferative intracellular signals and stimulates cell growth. These data implicate C. pneumoniae as a pathogenic mediator and a potential therapeutic target in the prevention of atherosclerotic disease.
A series of 11,890 patients from the senior investigator's surgical service between 1949 and 1998 is analyzed for the significance of distinct risk factors for recurrence of, and survival from, atherosclerotic occlusive disease. Eight risk factors have been assessed for their importance in 4 defined arterial categories (the coronary arterial bed, the branches of the aorta, the abdominal visceral [celiac, superior mesenteric, and renal] arteries, and the terminal abdominal aorta and its major branches) in determining survival rate of the entire group and their impact on rate of recurrence of atherosclerosis in a subgroup of 5,568 patients who had > or =1 postoperative arteriogram, permitting precise identification of changes in the atherosclerotic process. Patients in these 2 groups were followed for > or =25 years; univariate and multivariate analyses were used. On admission all patients had symptomatic atherosclerotic occlusive disease in a single vascular category. Each patient was treated surgically for alleviation of the disease. Two primary outcomes are included: (1) survival, by atherosclerosis category, in all 11,890 patients; and (2) recurrence, also by category, in the subset of 5,568 patients. Multivariate results for recurrence showed little consistency across categories. Only 1 risk factor, diabetes, appeared in 2 of the 3 categories fully analyzed. Other variables that are significant in only a single category are male sex, cholesterol, hypertension, and smoking. Survival showed much greater consistency, with age, diabetes, and hypertension significant in all 3 categories, male sex and smoking in 2, and cholesterol in only Category I. Univariate results followed much the same trend. For recurrence and survival, the response of the arterial bed to the risk factors in each of the 4 categories is distinctly different, an observation that we have not found to be previously reported.