Nobuo Negoro

Lovastatin inhibits gene expression of type-I scavenger receptor in THP-1 human macrophages.

Lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, inhibits the synthesis of mevalonic acid and is widely used as an anti-atherosclerotic drug. The macrophage scavenger receptor (SCR), a trimeric membrane glycoprotein, is postulated to play a key role in atheroma macrophage foam cell formation. HMG-CoA reductase is involved in the control of the synthesis of glycoproteins and farnesylated proteins, including ras proteins, which are involved in the transcriptional regulation of SCR gene expression. Accordingly, we examined whether lovastatin alters the gene expression of SCRs in THP-1 cell derived human macrophages. Lovastatin (5-15 microM) caused a significant dose-related reduction in steady state levels of type-I SCR mRNA in phorbol 12-myristate 13-acetate (PMA)-treated THP-1 cells. The addition of exogenous mevalonate (1 mM) completely restored the lovastatin-induced decrease of type-I SCR mRNA levels. While the addition of the isoprenoid end-product, isopentenyl adenine (50 microM), had little effect on the type-I SCR mRNA levels in lovastatin treated cells, the addition of isoprenoid farnesol (5 microM) largely restored the lovastatin-induced decrease of type-I SCR mRNA levels. Actinomycin D treatment showed that degradation rates of type-I SCR mRNA did not differ between the THP-1 derived cells with and without lovastatin treatment. Nuclear run-on assays showed that lovastatin markedly decreased the transcription of SCR gene in the cells. These results suggest that lovastatin inhibits the transcription of type-I SCR gene by affecting mevalonate metabolism, possibly through the farnesyl-pyrophosphate related end-product(s) in the THP-1-derived macrophages.

Differential diagnosis of fever in systemic lupus erythematosus using discriminant analysis

SummaryIn an attempt to find a reliable method to assess fever in patients with systemic lupus erythematosus (SLE), a multifactorial analysis was applied to the routine laboratory examinations, including white blood cell count (WBC) and serum globulin fraction concentrations. During 74 febrile episodes, 49 SLE patients showed increased disease activity and the remaining 25 febrile episodes were due to intercurrent infection. The two different groups of fever episodes were clearly separated by a principal component analysis using five variables from the routine laboratory tests, including WBC, serum alpha-1, alpha-2, beta, and gamma globulins. Discriminant analysis showed that 95% of 74 febrile episodes could be correctly classified as to the cause of fever when a combination of WBC and alpha-2 globulin level was used as variables. A simple discriminant formula which we calculated was considered to be of practical use for the differentiation of the two clinical entities.

Long-Term Effects of Calcium Antagonists and Angiotensin-Converting Enzyme Inhibitors in Patients with Chronic Renal Failure of IgA Nephropathy

Long-term effects of Ca antagonist and ACE inhibitor on renal function in hypertensive patients with chronic renal failure of IgA nephropathy were studied. Both Ca antagonists and ACE inhibitors were equally effective in reducing blood pressure.

Scleroderma-like reaction induced by uracil-tegafur (UFT), a second-generation anticancer agent

UFT, a combination of uracil and tegafur, is a second-generation anticancer agent. UFT has been used in Japan, other Asian countries, South America, and Russia. Recently, UFT has been extensively studied for colorectal, pancreatic, and various types of cancer in North America and Europe, especially with leukovorin. We report a case of a scleroderma-like reaction induced by long-term administration of UFT. This is the first report of UFT-induced scleroderma-like reaction.

Gene expression of endothelin receptors in aortic cells from cyclosporine-induced hypertensive rats.

1. We examined preproendothelin‐1, ETA and ETb receptor mRNA levels in aortic endothelial and smooth muscle cells from cyclosporine (CyA)‐induced hypertensive rats using the reverse transcription polymerase chain reaction method.

Clinical significance of von Willebrand factor in patients with adult dermatomyositis

Because the clinical significance of von Willebrand factor (vWF), a marker of endothelial injury, has not been well studied in adult patients with dermatomyositis (DM), we evaluated whether plasma vWF levels are useful as an index of disease activity in these patients. We measured plasma vWF antigen levels in 11 patients with active adult DM, 13 patients with inactive DM, and 18 healthy subjects using an enzyme-linked immunosorbent assay. The association of vWF level with clinical condition and muscle-derived enzyme leakage among DM patients was examined using analysis of covariance and logistic regression analysis. Furthermore, we studied the effects of treatment on the vWF antigen level. The mean vWF antigen level was significantly higher in active DM patients than in inactive DM patients and healthy subjects. Higher vWF levels were associated with clinical symptoms, such as general fatigue, fever, and muscle weakness. They were also associated with the levels of aspartate aminotransferase, alanine aminotransferase, and aldolase, but not with those of lactate dehydrogenase and creatine kinase (CK). vWF antigen was correlated with muscle enzymes except for CK. The plasma vWF levels in six patients with active DM significantly decreased after successful corticosteroid treatment. Plasma vWF level may be considered a useful marker of disease activity in adult DM patients.

Increased Na+/H+ exchange activity in vascular smooth muscle cells of spontaneously hypertensive rats and possible involvement of protein kinase C

1. Na+ influx into cultured vascular smooth muscle cells (VSMC) obtained from spontaneously hypertensive rats (SHR) and from Wistar‐Kyoto rats (WKY) was measured. Na+ influx via the Na+/H+ exchange system was measured as the rate of 22Na+ influx into cultured VSMC sensitive to ethylisopropylamiloride (EIPA), a specific inhibitor of the exchange system.

Plasminogen activation in plasma of patients with systemic lupus erythematosus

SummaryWe measured α2-plasmin inhibitor-plasmin complexes (PI-PC) in plasma of patients with systemic lupus erythematosus (SLE) to examine the plasminogen activation in SLE. The plasma PI-PC level in 23 patients with SLE was significantly higher than that in 18 normal subjects (P<0.001) and the SLE patients with nephrotic syndrome had higher plasma PI-PC levels than those without nephrotic syndrome (P<0.01). In addition, the plasma PI-PC level was significantly correlated with the level of plasma C3 breakdown products (iC3b/C3dg) in the patients with SLE (r=0.53, P<0.01). These results suggest that plasminogen is activated in plasma of patients with SLE and that the plasminogen activation may be associated with the activation of complement in SLE.

Angiotensin-converting enzyme inhibitor increases angiotensin type 1A receptor gene expression in aortic smooth muscle cells of spontaneously hypertensive rats

To examine the regulation of angiotensin receptors in vascular smooth muscle cells, we studied the effects of antihypertensive drugs on angiotensin type 1A (AT1A) receptor gene expression in aortic smooth muscle cells (ASMCs) from spontaneously hypertensive rats (SHRs) using both ribonuclease protection assay and reverse-transcription polymerase chain reaction. An increase in AT1A receptor gene expression in ASMCs of SHRs was induced by treatment with an angiotensin converting enzyme inhibitor (enalapril) for 2 weeks and 4 weeks, but not by other types of antihypertensive drugs such as alpha-blocker (doxazosin), alpha, beta-blocker (arotinolol), Ca antagonist (nicardipine) or vascular smooth muscle relaxant (hydralazine). Since all antihypertensive drugs lowered the blood pressure of the rats almost equally, our results suggest that AT1A receptor gene expression in ASMCs of SHRs may be regulated by the vascular renin-angiotensin system.

Expression of c-myc proto-oncogene in hearts and cultured smooth muscle cells of spontaneously hypertensive rats

We studied the expression of c-myc proto-oncogene in hearts and cultured aortic smooth muscle cells of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY), in order to investigate the association of the c-myc gene with cardiac hypertrophy and atherosclerosis in SHR. Transcription of the c-myc gene in hearts of SHR was higher than that of WKY at 10 weeks of age, when cardiac hypertrophy had developed in SHR. The c-myc gene expression in cultured aortic smooth muscle cells of SHR, after the addition of serum to the serum-deprived cultures, was higher than that of WKY. These results suggest that the enhanced expression of the c-myc gene in the hearts and cultured aortic smooth muscle cells of SHR may be associated with the growth control of these cells, and may play a role in the development of cardiac hypertrophy and atherosclerotic lesions in SHR.