Abstract-Glucocorticoid (GC) excess often elicits serious adverse effects on the vascular system, such as hypertension and atherosclerosis, and effective prophylaxis for these complications is limited. We sought to reveal the mechanism underlying GC-induced vascular complications. Responses in forearm blood flow to reactive hyperemia in 20 GC-treated patients were significantly decreased to 43Ϯ8.9% (meanϮSEM) from the values obtained before GC therapy (130Ϯ14%). An administration of vitamin C almost normalized blood flow responses. In human umbilical vein endothelial cells (HUVECs), production of hydrogen peroxide was increased up to 166.5Ϯ3.3% of control values by 10 Ϫ7 mol/L dexamethasone (DEX) treatment (PϽ0.01). Concomitant with DEX-induced hydrogen peroxide production, intracellular amounts of peroxynitrite significantly increased and those of nitric oxide (NO) decreased, respectively (PϽ0.01). Immunoblotting analysis using anti-nitrotyrosine antibody showed that peroxynitrite formation was increased in DEX-treated HUVECs. Using inhibitors against metabolic pathways for generation of reactive oxygen species (ROS), we identified that the major production sources of ROS by DEX treatment were mitochondrial electron transport chain, NAD(P)H oxidase, and xanthine oxidase. These findings suggest that GC excess causes overproduction of ROS and thereby perturbs NO availability in the vascular endothelium, leading to vascular complications in patients with GC excess. Key Words: glucocorticoid Ⅲ reactive oxygen species Ⅲ nitric oxide Ⅲ vascular endothelial function G lucocorticoid (GC) has being used widely for the treatment of patients with various disorders including autoimmune diseases, allergic diseases, and lymphoproliferative disorders. It has been well known, however, that GC therapy using prednisolone, methylprednisolone, or dexamethasone (DEX) is often limited by several adverse reactions associated with GC excess. 1,2 GC excess exhibits a variety of symptoms and signs, including truncal obesity with moon face, striae, hirsutism, cataract, osteoporosis, myopathy, diabetes mellitus, immunosuppression, and cardiovascular disorders such as hypertension and atherosclerosis. 3 Among these, cardiovascular complications are one of the important factors for predicting the morbidity and mortality of patients with GC excess. 3 Plasma volume expansion due to sodium retention plays a minor role, 1,2,4 and increased peripheral vascular resistance due in part to an increased pressor response to catecholamines and angiotensin II is shown to play a major role in the pathogenesis of hypertension induced by GC excess. 1,2,5 However, the molecular mechanism whereby GC excess causes the increase in vascular resistance remains unclear.Vascular endothelial cells regulate vascular tone through the release of a variety of relaxing and contracting factors that modulate the contractile activity of vascular smooth muscle cells. 6,7 Nitric oxide (NO), an endothelial cell-derived relaxing factor, is thought to be the most important vaso...
Corticosteroid myopathy is a major clinical problem in patients undergoing chronic corticosteroid treatment and shows insidious and progressive muscle atrophy in proximal limbs. Although several mechanisms underlying the pathophysiology of muscle injury have been postulated, precise pathogenesis is still not clear. We evaluated the mitochondrial functions in patients receiving corticosteroids compared with those in healthy controls or patients not receiving corticosteroids. The serum levels and total production of lactate were investigated by an aerobic exercise test using a bicycle ergometer. Mitochondrial respiratory activities and oxidative damage in biopsied skeletal muscles were also studied. The results of aerobic exercise tests revealed a significant overproduction of lactate in patients treated with corticosteroids ( p < 0.005), which was positively correlated with total corticosteroid doses administered ( p < 0.0001). In these patients, mitochondrial enzyme activity in complex I was significantly decreased ( p < 0.05) and oxidative damage of biopsied skeletal muscle was remarkable both in mitochondrial and nuclear DNAs ( p < 0.001). The results suggest that chronic corticosteroid administration induces mitochondrial dysfunction and oxidative damage in skeletal muscles, which may be the pathogenesis, at least in part, of corticosteroid-induced myopathy.
Background: Increased serum lipoprotein(a) [Lp(a)] is an independent risk factor for atherosclerosis. We previously reported that aspirin reduced Lp(a) production by cultured hepatocytes via the reduction of apolipoprotein(a) [apo(a)] gene transcription. Methods: We evaluated both the effect of aspirin treatment (81 mg/day) on serum Lp(a) concentrations and the correlation between the degree of reduction in serum Lp(a) and the type of apo(a) isoform in 70 patients with coronary artery disease or cerebral infarction. Results: Aspirin lowered serum Lp(a) concentrations to ∼80% of the baseline values in patients with high Lp(a) concentrations (>300 mg/L). The percentage of decrease in serum Lp(a) was larger in patients with high Lp(a) than in patients with low Lp(a) (<300 mg/L), irrespective of apo(a) isoform size. The decreases in serum Lp(a) in high Lp(a) patients with both the high-molecular-weight and the low-molecular-weight isoforms were positively correlated with the baseline Lp(a) concentrations. Conclusions: Because the secretory efficiencies of apo(a) in the same isoform are likely to be similar, the difference in serum Lp(a) concentrations in patients having the same apo(a) isoform depends on the transcriptional activity of the apo(a) gene. These findings suggest that aspirin decreases serum Lp(a) concentrations via a decrease in apo(a) gene transcription more effectively in patients with high transcriptional activity of this gene.
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