Background-Pulmonary arterial hypertension (PAH) is a hyperproliferative vascular disorder observed predominantly in women. Estrogen is a potent mitogen in human pulmonary artery smooth muscle cells and contributes to PAH in vivo; however, the mechanisms attributed to this causation remain obscure. Curiously, heightened expression of the estrogenmetabolizing enzyme cytochrome P450 1B1 (CYP1B1) is reported in idiopathic PAH and murine models of PAH. Methods and Results-Here, we investigated the putative pathogenic role of CYP1B1 in PAH. Quantitative reverse transcriptionpolymerase chain reaction, immunoblotting, and in situ analysis revealed that pulmonary CYP1B1 is increased in hypoxic PAH, hypoxicϩSU5416 PAH, and human PAH and is highly expressed within the pulmonary vascular wall. PAH was assessed in mice via measurement of right ventricular hypertrophy, pulmonary vascular remodeling, and right ventricular systolic pressure. Hypoxic PAH was attenuated in CYP1B1 Ϫ/Ϫ mice, and the potent CYP1B1 inhibitor 2,3Ј,4,5Ј-tetramethoxystilbene (TMS; 3 mg ⅐ kg Ϫ1 ⅐ d

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1. A study was undertaken to investigate the distribution of ascorbic acid between various cellular components of blood, in normal individuals, and its relation to the plasma concentration. Forty-one unsupplemented individuals and sixteen supplemented (2 g/d for 5 d) individuals were studied.2. Granulocytes, mononuclear leucocytes, platelets and erythrocytes were separated by differential sedimentation and centrifugation. Ascorbic acid contents were measured by the dinitrophenylhydrazine method. 3. Ascorbic acid content per cell was higher in mononuclear leucocytes and granulocytes than in platelets and erythrocytes. Intracellular ascorbic acid concentrations, calculated from published values for cell volumes, when compared with the plasma concentration showed a marked ability to concentrate ascorbic acid in mononuclear leucocytes (80 times), platelets (40 times) and granulocytes (25 times).4. Erythrocytes showed little ability to concentrate ascorbic acid over the normal range of plasma concentration but because of their relative numbers they and the plasma fraction accounted for most of the blood-borne ascorbic acid (> 70%). 5. The ascorbic acid content of granulocytes, platelets and erythrocytes showed a significant positive correlation with the plasma concentration and supplementation with ascorbic acid significantly increased the content of these cell types. Mononuclear leucocytes in contrast did not show any such relationship.6. The ability of the mononuclear leucocytes to maintain the highest levels of ascorbic acid in the cell types studied, despite variation in plasma availability, warrants further study, particularly in view of the importance of these cells in immunocompetence.

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