Akihiko Yoneyama

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.

EFFECTS OF DEHYDROEPIANDROSTERONE ON MITOGEN-ACTIVATED PROTEIN KINASE IN HUMAN AORTIC SMOOTH MUSCLE CELLS

The objective of the present study was to determine whether dehydroepiandrosterone (DHEA) modifies growth factor-induced mitogen-activated protein kinase (MAPK) activation, based on our previous study demonstrating that DHEA attenuates fetal calf serum-induced proliferation in human male aortic smooth muscle cells (human male aortic SMCs). Human male aortic SMCs were used for this study. Platelet-derived growth factor-BB (PDGF-BB), epidermal growth factor (EGF), and basic fibroblast growth factor (bFGF), but not insulin-like growth factor-1 (IGF-1), stimulated MAPK activity. Only MAPK activation induced by PDGF-BB was reduced by pretreatment with DHEA, although DHEA did not affect the MAPK activation induced by EGF or bFGF. The basal and PDGF-stimulated MAPK activity were decreased by two types of cyclic AMP (cAMP) elevating agents and increased by cAMP-dependent protein kinase (PKA) inhibitor in human male aortic SMCs, suggesting that cAMP regulates MAPK negatively. The intracellular cAMP was increased by PDGF-BB. The increase of cAMP by PDGF-BB was augmented by pretreatment with DHEA, although DHEA alone did not affect cAMP. Neither EGF nor bFGF affected cAMP with and without DHEA pretreatment. Secretion of PGE2 induced by PDGF was augmented by pretreatment with DHEA. Stimulatory effects of DHEA on the production of PGE2 and cAMP were partially canceled by aromatase inhibitor and completely canceled by indomethacin or selective inhibitor of cyclooxygenase-2. These results suggest that DHEA inhibited MAPK activation induced by PDGF-BB via PGE2 overproduction and subsequent cAMP-dependent pathway in human male aortic SMCs.

Takayasu's arteritis accompanied with massive pericardial effusion--a case report.

A 40-year-old woman who had been treated for Takayasus arteritis was admitted to the hospital with fever, fatigue, malaise, and severe chest pain. Computed tomography of the chest demonstrated massive pericardial effusion and bilateral pleural effusion. In laboratory data, the C-reactive protein was high at 22.0 mg/dL, and erythrocyte sedi mentation rate was also high at 80 mm/hr. The diagnosis was pericarditis with a recur rence of the systemic inflammatory process of Takayasus arteritis. The patient was treated with methylprednisolone pulse therapy. Her massive pericardial effusion disap peared without pericardiocentesis.

Decrease in plasma cholesteryl-ester transfer protein activity with simvastatin treatment in patients with type IIa hypercholesterolemia

Abstract We studied the effects of simvastatin treatment on plasma cholesterylester transfer protein (CETP) activity and lipid levels in patients with type IIa hypercholesterolemia. We treated 24 patients, 4 men and 20 women aged 49 to 81 years (mean age, 64.5 ± 8.5 years), with simvastatin at a daily dose of 5 mg for 4 weeks. Simvastatin treatment significantly decreased plasma total cholesterol (262 ± 28 mg/dL vs 220 ± 28 mg/dL) and low-density lipoprotein cholesterol (LDL-C)(181 ± 26 mg/dL vs 135 ± 28 mg/dL) and significantly increased high-density lipoprotein cholesterol (HDL-C) (57.2 ± 8.4 mg/dL vs 62.8 ± 10.5 mg/dL. CETP activity significantly decreased after 4 weeks of treatment (11.2 ± 3.8%/10 μL/3 h vs 8.9 ± 3.8% 10 μL/3 h. These results suggest that one of the lipid-lowering effects of simvastatin is due to decreased CETP activity, which results in decreased LDL-C and increased HDL-C concentrations.

Increase in plasma high-density lipoprotein2b subclass protein concentration after pravastatin treatment in patients with hypercholesterolemia

Abstract To determine the effects of pravastatin on plasma lipid levels, on low-density lipoprotein (LDL), and high-density lipoprotein (HDL) particle size and HDL subclass protein concentration, we studied 31 patients with hypercholesterolemia (9 men and 22 women, aged 36 to 79 years [mean age, 61.5 ± 10.3 years]). Patients were treated with pravastatin 10 mg daily for 12 weeks. After treatment, plasma levels of LDL cholesterol were significantly reduced (from 197 ± 60 to 149 ± 56 mg/dL), plasma levels of total cholesterol were significantly reduced (from 281 ± 58 to 237 ± 51 mg/dL), and levels of HDL 2b subclass protein were significantly increased (from 1.24 ± 0.24 to 1.35 ± 0.23 mg/protein/mL). Significant differences were not noted in the level of HDL cholesterol, LDL peak particle diameter, and the activity of lecithin-cholesterol acyltransferase and cholesteryl-ester transfer protein before and after treatment. The effect of pravastatin on lipoprotein concentration and particle size will need to be confirmed in studies with larger numbers of patients with various lipoprotein abnormalities.

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.