Noboru Yoshimine

Dexamethasone-induced suppression of aortic atherosclerosis in cholesterol-fed rabbits. Possible mechanisms.

We investigated the mechanisms by which corticosteroids affect atherosclerosis. Male New Zealand White rabbits were injected with 0.125 mg dexamethasone (n = 10) or vehicle (control group, n = 10). Both groups were fed a 1% cholesterol diet for 8 weeks. Although the dexamethasone-treated animals exhibited a greater degree of hyperlipidemia, they exhibited significantly less atherosclerotic plaque of the aortic surface than control animals (7.8% versus 47.2%). Immunofluorescence study of the aortic plaque specimens showed that dexamethasone administration reduced both macrophages and T lymphocytes. In vitro, dexamethasone suppressed the proliferation and differentiation of U937 cells and inhibited uptake and degradation of beta-very low density lipoproteins by mouse peritoneal macrophages. These findings suggest that dexamethasone suppresses the development of atherosclerosis in the aorta of rabbits by inhibiting recruitment and proliferation of macrophages and the formation of foam cells in plaques.

Serum lipid peroxide assayed by a new colorimetric method

Serum lipid peroxide (LPO) in 72 healthy male subjects was studied using a newly developed assay method based on the reaction of LPO with methylene blue derivative (MCDP; 10-N-Methylcarbamoyl-3,7-dimethylamino-10 H-phenothiazine). This method is specific for lipid hydroperoxide and the relation is equimolar. The value obtained was 7.63 +/- 2.78 nmol/ml. Positive correlations were observed between LPO and height (r = 0.290), body weight (r = 0.244) and hemoglobin (r = 0.248). However, no significant correlation was observed between serum LPO level and other clinical data, including age. In addition, serum LPO value measured by this method did not show significant correlation with that measured by the thiobarbituric acid method in rat serum. This discrepancy might be due to the differences in substrates measured by each method.

Substrate-bound fibrinogen, fibrin and other cell attachment-promoting proteins as a scaffold for cultured vascular smooth muscle cells

We have previously reported that fibrinogen/fibrin can induce the migration of vascular smooth muscle cells in vitro. In this study, we examined the effect of substrate-bound fibrinogen/fibrin and other cell attachment-promoting proteins on the adhesion of vascular smooth muscle cells. The amount of fibrinogen/fibrin adsorbed to plastic wells and the adhesion of smooth muscle cells to the wells were found to depend on the concentration of fibrinogen used for coating the wells. The effect of fibrinogen/fibrin was comparable to that of so-called cell attachment-promoting proteins (fibronectin, vitronectin, and type I collagen). Adhesion of smooth muscle cells to fibrinogen/fibrin-coated wells was inhibited by the synthetic peptide GRGDS, but not by a control peptide, GRGES. Vitronectin, fibronectin, type I collagen, denatured type I collagen and commercial gelatin also induced smooth muscle cell adhesion. The adhesion induced by vitronectin, denatured type I collagen, and commercial gelatin was inhibited by GRGDS. However, the adhesion induced by type I collagen was not influenced and that induced by fibronectin was only slightly inhibited. These observations suggest that fibrinogen/fibrin deposited extracellularly in the arterial intima may act as a scaffold in the process of smooth muscle cell migration.

Ineffectiveness of Ca2+-antagonists nicardipine and diltiazem on experimental atherosclerosis in cholesterol-fed rabbits.

There is accumulating evidence that calcium metabolism plays an important role in the pathogenesis of atherosclerosis. The inhibitory effect of nifedipine, a Ca2-antagonist, on experimental atherosclerosis in cholesterol-fed rabbits has been reported, and we examined the anti-atherosclerotic action of nicardipine and diltiazem, similar Ca2+-antagonists, but no inhibitory action was observed. It is necessary to recognize the fact that the sensitivity of rabbits to an antiatherogenic diet shows great individual differences. For the purpose of preventing atherosclerosis due to the abnormality of lipid metabolism the use of Ca2+-antagonist is not warranted at the present stage.

Ineffectiveness of Ca2+-antagonists nicardipine and diltiazem on experimental atherosclerosis in cholesterol-fed rabbits

There is accumulating evidence that calcium metabolism plays an important role in the pathogenesis of atherosclerosis. The inhibitory effect of nifedipine, a Ca2-antagonist, on experimental atherosclerosis in cholesterol-fed rabbits has been reported, and we examined the anti-atherosclerotic action of nicardipine and diltiazem, similar Ca2+-antagonists, but no inhibitory action was observed. It is necessary to recognize the fact that the sensitivity of rabbits to an anti-atherogenic diet shows great individual differences. For the purpose of preventing atherosclerosis due to the abnormality of lipid metabolism the use of Ca2+-antagonist is not warranted at the present stage.

Effects of an oral glucose load on serum immunoreactive insulin, free fatty acid, growth hormone and blood sugar levels in young and elderly subjects.

In 29 healthy young adults and 22 ambulatory elderly subjects, a study was made of the effects of an oral glucose load on the levels of serum immunoreactive insulin (IRI), free fatty acids (FFA), growth hormone (HGH) and blood glucose. In the elderly, the pre‐load blood glucose and serum IRI levels were higher than in the younger group, reached the peak more gradually, and took longer to return to the baseline values. There was no significant difference in the serum FFA levels between the two groups until 3 hours after the glucose load, at which time the FFA values had returned to the fasting level in the young subjects but remained depressed in the elderly subjects. Serum HGH fasting levels in the elderly males were significantly higher than in the younger males and remained so at 1–2 hours after the glucose load. For the females, the numbers were too small and the intragroup variability too great to permit drawing conclusions. The total findings lend support to Dilmans hypothesis of a genetically programmed elevation of the hypothalamic threshold to feedback suppression, with age.

Comparative toxicity of oxidatively modified low-density lipoprotein and lysophosphatidylcholine in cultured vascular endothelial cells

SummaryOxidative modification of low-density lipoprotein (LDL) may play an important role in the initiation and progression of atherosclerosis. We previously showed that the cytotoxicity of oxidized LDL (oxLDL) depended on the level of lipid hydroperoxides. Meanwhile, it has been shown that during LDL oxidation, a significant part of the LDL phosphatidylcholine (PC) is degraded to lysophosphatidylcholine (LPC) by an intrinsic phospholipase A2-like activity, and that LPC is toxic to various cells. In the present study, we compared the toxicity of oxLDL with that of LPC in cultured bovine aortic endothelial cells. Cytotoxicity induced by LPC, assessed by the release of lactate dehydrogenase (LDH), reached a plateau within 1h. LDH release induced by oxLDL occurred much later, at about 3h, and increased linearly until nearly all the LDH was released at 10h. The addition of deferoxamine, a Fe3+ chelator, to the reaction medium prevented the toxic effects of oxLDL, but not of LPC. Native LDL and oxLDL inhibited the toxicity of LPC, while native LDL promoted the toxicity of oxLDL. Albumin inhibited the toxicity of LPC but not of oxLDL. Preincubation of endothelial cells with an antioxidant, probucol, protected against oxLDL toxicity, but not against LPC toxicity. These results suggest that lipid hydroperoxides associated with the oxLDL particle, not LPC, constitute the toxic moiety of oxLDL. These substances may generate lipid peroxyl and alkoxyl radicals in the presence of ionic iron, probably from intracellular iron stores in endothelial cells, and produce cytotoxicity.

Hemodialysis and the elderly patient: Retrospective analysis of morbidity and mortality

Elderly hemodialysis patients receiving maintenance hemodialysis were studied retrospectively, with special reference to survival rates, morbidity, and response to rehabilitation. The 5-year survival rates were calculated in 43 elderly patients who were 65 years or older at the start of hemodialysis, and compared with those in 171 younger patients who were under 65 years of age at the start of hemodialysis. The cumulative actuarial 5-year survival rate for the elderly patients was 39.8%, significantly lower than the 79.2% for the younger controls (p<0.001). Cardiovascular disease and infection accounted for 41.9% and 23.3% of the deaths in elderly patients similar to findings in younger controls. However, the incidence of death due to cerebral infarction was significantly higher in the elderly (p<0.05). For the elderly in 1991, the hospital days/patient and the frequency of admissions/patient were two and three fold those of younger controls. Admissions due to infection significantly exceeded those in the younger controls. We found that 33 elderly patients with impaired activities of daily living showed a significant improvement in their Barthel index scores after 2.2 months of participation in a rehabilitation program (p<0.001), which was designed to increase their ability to stand and walk unaided. The elderly hemodialysis patients had a higher rate of mortality and morbidity with more frequent, and lengthier hospitalizations than the younger patients because of the prevalence of complications. Despite their lower survival rates, elderly patients receiving hemodialysis can be managed without serious impairment especially if aided by a rehabilitation program.

The effects of aspirin ingestion of blood fibrinolysis, glucose, and immunoreactive insulin levels in man.

females were pregnant or on oral contraceptives at the time of the study; none had undergone hysterectomy. After an overnight fast during which smoking was prohibited, fasting blood samples were drawn and analyzed as follows: Blood glucose concentration was determined by the method of Somogyi-Nelson8; immunoreactive insulin levels (IRI) were determined by the method of Hales and Randle.9 Free fatty acid levels (FFA) were estimated by the method of Antonis adapted for the autoanalyzerl°; growth hormone levels (HGH) were assayed by the double antibody technic of Schalch and Parker.ll Euglobulin lysis times (ELT) were measured by the method of von Kaulla 12 with the minor modifications em-

Alterations of lipid peroxide levels in the plasma and erythrocyte ghosts under treatment with simvastatin

Simvastatin, an HMG-CoA reductase inhibitor, was administered to nine patients with hypercholesterolemia, and changes in the serum lipid levels as well as erythrocyte ghost lipid peroxide levels were examined at 0, 16, 32, and 48 weeks. The serum TC, apo-B, LDL-C, and EG-LPO levels were reduced significantly at 16 and 48 weeks, whereas no remarkable changes were observed in the serum TG, HDL-C, Lp(a), apo-A1, A2, C2, C3, E, or serum lipid peroxide levels. These findings suggest that simvastatin not only improves serum lipid levels but also inhibits lipid peroxidation of the erythrocyte membranes, and might be useful for preventing the progression of atherosclerotic vascular lesions.