Masanobu Kawaguchi

Effects of dehydroepiandrosterone on proliferation of human aortic smooth muscle cells

Dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) have been shown to be associated with the progression of coronary atherosclerosis in clinical and in vivo studies. However, the mechanisms responsible for the association have not been determined. In the present study, we found that DHEA influences the in vitro growth of vascular smooth muscle cells obtained from the human aorta (hASMC). The concentrations of DHEA ranging from 10(-8) M to 10(-6) M significantly stimulated the mitogenesis of hASMC in serum-free culture. On the other hand, 4 hrs of pretreatment with DHEA attenuated the fetal calf serum induced proliferative effect in a dose-dependent manner. However, the in vitro effects of DHEA on the mitogenesis observed in hASMC were not seen in rat-derived aortic smooth muscle cell lines (A10 cells). With respect to DHEAS, the hormone, at concentrations up to 10(-5) M did not affect the growth of either hASMC or A10 cells in vitro. The growth response of hASMC to DHEA in vitro was markedly affected by the culture conditions. The differential proliferative effects of DHEA on smooth muscle cells between rat and human are of interest. We conclude that the effects of DHEA on mitogenesis of hASMC may, at least in part, explain the association between DHEA and atherosclerosis.

Coexisting type III hyperlipoproteinemia and familial hypercholesterolemia: A case report

A 39-year-old man presented with type III hyperlipoproteinemia in association with heterozygous familial hypercholesterolemia (FH). He had extensive tuberous xanthomas over the knees and elbows and xanthomas in the Achilles tendons. He also had palmar xanthomas. He exhibited severe hypercholesterolemia and hypertriglyceridemia. This patient was heterozygous for FH, as evidenced by low low-density lipoprotein (LDL) receptor function on lymphocytes, and had type III hyperlipoproteinemia, as determined by apolipoprotein (apo) E phenotype 2/2 in isoelectric focusing of the E isoproteins and the presence of a broad beta band on electrophoresis. Because therapy consisting of diet restrictions and lipid-lowering agents such as clinofibrate and niceritrol did not decrease serum total cholesterol ([TC] 15.26 mmol/L) and triglyceride ([TG] 10.79 mmol/L) levels effectively, the patient underwent plasmapheresis once every 2 weeks using a dextran sulfate-cellulose column. Repeated plasmapheresis markedly reduced serum TC and TG and induced complete regression of the palmar xanthoma after 6 months. The severity of tuberous xanthomas on the knees and elbows was reduced after 2.5 years. After plasmapheresis, TC decreased to 1.94 mmol/L from 10.40 mmol/L and TG decreased to 0.33 mmol/L from 7.90 mmol/L. Plasmapheresis performed with a dextran sulfate-cellulose column was highly effective in removing the lipoprotein-remnant particles in this patient, leading to generalized improvement in the lipoprotein profile.

Increased content of epidermal growth factor in platelet lysates in non-insulin-dependent diabetes mellitus

We evaluated the content of EGF in platelet lysates obtained from 49 patients with non-insulin-dependent diabetes mellitus (NIDDM)(18 males, 31 females, age 58 +/- 13 years) and from 23 clinically healthy control subjects (11 males, 12 females, age 53 +/- 18 years). Platelets were collected from platelet-rich plasma and lysed. EGF was determined by radioimmunoassay. The immunoreactive EGF content in the platelet lysates in diabetic patients significantly exceeded that of control subjects (44.9 +/- 18.5 pg/mm3platelet vs. 34.2 +/- 7.8 pg/mm3platelet, mean +/- SD p < 0.008). In performing multiple regression analysis with ten clinical parameters, urinary albumin excretion (F = 16.1, r = 0.551, p < 0.001), duration of diabetes (F = 13.0, r = 0.511, p < 0.001) and the presence of diabetic proliferative retinopathy (F = 8.8, p < 0.01) were significantly associated with irEGF content in platelet lysates. These observations suggest that the amount of EGF in platelets may increase with the progression of diabetic complications. The mechanism for the increase of EGF in platelets remains to be clarified.

Excretion of urinary epidermal growth factor in non-insulin dependent diabetes mellitus

Morning urine samples were assayed for human EGF (hEGF) in 137 non-insulin dependent diabetic patients with normal serum creatinine and beta 2-microglobulin levels. Serving as controls, 80 age- and sex-matched healthy subjects were also examined. A significant positive correlation between hEGF excretion and the level of hemoglobin A1C (HbA1c) was present in those patients with a HbA1c value exceeding 8% (r = 0.37; p = 0.003) but not in the overall patients. The urinary hEGF level did not correlate with the concentration of glucose in urine or plasma. The mean urinary hEGF level of diabetic patients was significantly lower than that of healthy subjects. The mean urinary hEGF level was significantly lower in the patients with a diabetic history that exceeded five years as compared with those with a history below five years. The mean urinary hEGF level was significantly lower in the patients with retinopathy vs. those without retinopathy. In the patients with HbA1c value below 8%, the mean urinary hEGF level was lower in the patients whose urinary albumin level exceeded 1.7 mg/mmol.creatinine as compared with those whose urinary albumin excretion was below 1.7 mg/mmol.creatinine. These findings suggest that urinary hEGF excretion may decrease with the progression of diabetic complications in the patients with well-controlled glycemia, and that inadequate glycemic control may lead to an increased excretion of urinary hEGF in the early disease stage.

Increased serum triglyceride clearance, unchanged cholesteryl ester transfer protein activity, and elevated HDL cholesterol during treatment of hypertriglyceridemia with bezafibrate

The effects of bezafibrate on lipid metabolism were evaluated in 22 patients with type IIb or type IV hypertriglyceridemia. Bezafibrate 400 mg/d was administered for 8 weeks. A fat emulsion tolerance test (FETT) to evaluate serum triglyceride (TG) clearance (fractional removal rate = K2) and measurement of cholesteryl ester transfer protein (CETP) activity were performed before bezafibrate administration and after the 8-week treatment period using blood samples obtained after overnight fasting. Statistically significant reductions were observed in serum TG (P < 0.01), apolipoprotein (apo) B (P < 0.01), apo C-II (P < 0.05), apo C-III (P < 0.001), and apo E (P < 0.05). Significant increases were seen in high-density lipoprotein cholesterol (HDL-C) (P < 0.001), apo A-I (P < 0.001), and apo A-II (P < 0.001). K2 was significantly elevated (P < 0.001). CETP activity declined slightly, but the change was not statistically significant. Strong positive correlations were evident between the absolute value of increased K2 and the increase in both HDL-C (r = .67, P < 0.005) and apo A-I (r = .53, P < 0.05). It can be inferred from these findings that the bezafibrate-induced reduction in serum TG and increase in HDL-C observed in patients with hypertriglyceridemia arise from an acceleration in TG-rich lipoprotein metabolism.

Effects of fructose ingestion on sorbitol and fructose 3-phosphate contents of erythrocytes from healthy men

To investigate the effect of fructose ingestion on sorbitol and fructose 3-phosphate (F3P) in erythrocytes, we administered 50 g fructose with and without treatment with an aldose reductase inhibitor, epalrestat, to seven healthy, normal-glucose-tolerant, male volunteers aged 20–43 years. The same subjects were given 50 g glucose on another day. The sorbitol and F3P contents in their erythrocytes increased significantly, reaching peak levels at 60 min and 180 min, respectively, following fructose ingestion. On the other hand, glucose ingestion did not cause any statistically significant change in sorbitol content in their erythrocytes, although it significantly elevated their F3P content. Treatment with epalrestat had no significant effect on incremental changes in erythrocyte sorbitol and F3P content following fructose ingestion. This suggests that oral fructose may be converted directly to sorbitol and F3P in erythrocytes instead of being converted via glucose. Thus, the dietary intake of fructose may affect the concentrations of sorbitol and F3P in erythrocytes in normal men.

Effect of ascorbic acid on pituitary prolactin secretion in the non-ascorbate synthesizing osteogenic disorder shionogi (ODS) rat

We examined the secretion of prolactin (PRL) in the hereditary scurvy-prone Osteogenic Disorder Shionogi (ODS) rat to investigate the role of ascorbic acid (AsA) in pituitary lactotroph and hypothalamic function. Plasma PRL concentrations of conscious AsA-deficient or control ODS rats were measured before and after the administration of metoclopramide (MCP), 5-hydroxy-L-tryptophan (5-HTP) or saline. The basal plasma PRL levels did not differ between the two groups. However, the AsA-deficient rats exhibited significantly larger changes in plasma prolactin concentration in response to MCP or 5-HTP than the control ODS rats. Thus, AsA deficiency enhanced the stimulated, but not the basal, secretion of PRL in ODS rats. Our findings suggest that AsA may have an inhibitory effect on PRL secretion.

Improvement in hyperchylomicronemia, transient deficiency in lipoprotein lipase and hepatic triglyceride lipase activity, and diabetes mellitus produced by pravastatin and bezafibrate: a case report

Abstract A 50-year-old Japanese woman with type IV hyperlipidemia was placed on a low-fat diet. This regimen was minimally effective, so lipid-lowering drugs (clinofibrate [600 mg/d] and niceritrol [750 mg/d]) were added. However, hypertriglyceridemia worsened and diabetes mellitus appeared. She then developed xanthomatous eruptions, type V hyperlipidemia, reduced postherapin plasma lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activity. She was admitted to the hospital, and previous drug therapy was stopped. Dietary control and administration of the antihyperlipidemic agents pravastatin (10 mg/d) and bazafibrate (400 mg/d) led to the gradual recovery of postheparin plasma LPL and HTGL activity, conversion of type V hyperlipidemia to type IV hyperlipidemia, the disappearance of xanthomatous eruptions, and concurrent improvement in diabetes mellitus.