Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tetrandrine, a purified traditional Chinese medicinal herb that acts as an immunosuppressant and a Ca2+ channel blocker, has been clinically used to treat patients with arthritis, silicosis and hypertension. Since T cells play a critical role as autoreactive and pathogenic population in autoimmune diseases, in this study, we examined the immunosuppressive effect of tetrandrine on human peripheral blood T cells. We showed that tetrandrine inhibited phorbol 12-myristate 13-acetate (PMA) + ionomycin-induced T cell proliferation, interleukin-2 secretion and the expression of the T cell activation antigen, CD71. Further investigation of the molecular mechanism demonstrated that tetrandrine inhibited the expression of the protein kinase C-dependent interleukin-2 receptor alpha chain and CD69 but not the expression of the Ca2+-dependent CD40 ligand and CD69. Interestingly, when tetrandrine and cyclosporin A were added together, significant synergism in the suppression of T cell activation was observed. Moreover, of the several tetrandrine analogues studied, hernandezine was the most potent inhibitor of protein kinase C signaling events. These results also suggest that the protein kinase C-inhibitory capacity of tetrandrine and its analogues may not be associated with their function as Ca2+ channel blockers. Lastly, we showed that, within therapeutic concentrations, tetrandrine and its analogues could induce cellular apoptosis, which is defective in autoimmune diseases. In conclusion, our findings provide novel information about the molecular mechanism of the immunosuppressive effect of tetrandrine and its analogues in human peripheral blood T cells.
 ...
PMID:Plant alkaloid tetrandrine downregulates protein kinase C-dependent signaling pathway in T cells. 1007 15

This project was designed to investigate the application of bone marrow transplantation to a progressive and ultimately fatal systemic autoimmune disease. Male (NZW x BXSB)F1 (W/BF1) mice develop acute systemic autoimmune disease characterized by degenerative coronary vascular disease (CVD) with myocardial infarctions, hypertension, thrombocytopenia, glomerulonephritis, and persistently elevated levels of circulating immune complexes. After preliminary studies established the onset of disease between 10 and 12 weeks of age, 6- to 8-week-old male W/BF1 mice were targeted for transplantation with either T-cell-depleted bone marrow or purified hematopoietic stem cells from haploidentical B6C3/F1 mice. Posttransplantation flow cytometric analysis of splenocytes demonstrated donor phenotypes in W/BF1 recipient mice that had received T-cell-depleted marrow or hematopoietic stem cell preparations (lineage negative, CD71 negative) from B6C3/F1 donors. Survival of W/BF1 mice transplanted with bone marrow from normal B6C3/F1 donors was very high, and assessment at 100 days after transplantation revealed reduction in onset and severity of disease. Autoantibodies to cardiolipin and double-stranded DNA were markedly reduced to levels present in normal mice. Immunohistochemistry of heart and kidney tissue revealed significant amelioration of degenerative CVD and glomerulonephritis in the majority of W/BF1 recipients of marrow transplants from B6C3/F1 donors. All engrafted W/BF1 mice displayed normal immunologic competence 100 days posttransplantation.
 ...
PMID:Prevention of coronary vascular disease by transplantation of T-cell-depleted bone marrow and hematopoietic stem cell preparation in autoimmune-prone w/BF(1) mice. 1106 80

Cells respond to mechanical stimuli with diverse molecular responses. The nature of the sensory mechanism involved in mechanotransduction is not known, but integrins may play an important role. The integrins are linked to both the cytoskeleton and extracellular matrix, suggesting that probing cells via integrins should yield different mechanical properties than probing cells via non-cytoskeleton-associated receptors. To test the hypothesis that the mechanical properties of a cell are dependent on the receptor on which the stress is applied, human aortic smooth muscle cells were plated, and magnetic beads, targeted either to the integrins via fibronectin or to the transferrin receptor by use of an IgG antibody, were attached to the cell surface. The resistance of the cell to deformation ("stiffness") was estimated by oscillating the magnetic beads at 1 Hz by use of single-pole magnetic tweezers at 2 different magnitudes. The ratio of bead displacements at different magnitudes was used to explore the mechanical properties of the cells. Cells stressed via the integrins required approximately 10-fold more force to obtain the same bead displacements as the cells stressed via the transferrin receptors. Cells stressed via integrins showed stiffening behavior as the force was increased, whereas this stiffening was significantly less for cells stressed via the transferrin receptor (P<0.001). Mechanical characteristics of vascular smooth muscle cells depend on the receptor by which the stress is applied, with integrin-based linkages demonstrating cell-stiffening behavior.
Hypertension 2001 Nov
PMID:Receptor-based differences in human aortic smooth muscle cell membrane stiffness. 1171 14

An increased level of soluble transferrin receptor (sTfR) has been recognized as a useful indicator of iron deficiency, especially in tumour anaemia and in chronic diseases. In cases of erythropoietin substitution, however, it indicates a successful stimulation of erythropoiesis. We report an "unusual" increase in sTfR in a 60-year-old man who suffered from end-stage hypernephroma with extended lung metastases. He showed pulmonal hypertension, polycythaemia and a high serum level of erythropoietin. We assume that, in this case, the increased sTfR originates not only from bone marrow but could be partly contributed also by the malignant tissue of the hypernephroma.
 ...
PMID:Increased soluble transferrin receptor in a case of hypernephroma accompanied by polycythaemia and elevated erythropoietin. 1238 76

The development of a non-invasive method of prenatal diagnosis in maternal blood has been the goal of our investigations during the last years. We have developed several anti-CD71 monoclonal antibodies and optimized a protocol for the isolation of nucleated red blood cells (NRBC) from peripheral maternal blood. The enhanced traffic of fetal erythroblasts into the maternal circulation in preeclampsia has been investigated by several groups. In this study, we compared one of our antibodies, 2F6.3, with a commercial anti-CD71 antibody in blood samples from pregnant women suffering pregnancy-induced hypertension (PIH) and in a control group of pregnant women without clinical features suggestive of an increased risk of developing preeclampsia. The mAb 2F6.3, developed by our group, has succeeded in isolating a significantly higher number of erythroblasts with less maternal cell contamination than the commercial antibody in both women with PIH and in the control group (p<0.01; Wilcoxon Signed Ranks Test). Fluorescence in situ hybridization analysis also demonstrated that 2F6.3 is a better antibody for the isolation of fetal NRBC in maternal blood than the commercial anti-CD71 antibody.
 ...
PMID:A monoclonal antibody with potential for aiding non-invasive prenatal diagnosis: utility in screening of pregnant women at risk of preeclampsia. 1575 16

There is increasing evidence that moderately elevated body iron stores, below levels commonly found in genetic hemochromatosis, may be associated with adverse health outcomes. Genetic hemochromatosis, characterized by transferrin saturation (TS) greater than 45%, is most often linked to homozygosity of the HFE C282Y allele. The phenotype is also modulated by mutations of more recently discovered genes (including ferroportin, hemojuvelin, hepcidin, and transferrin receptor) and environmental factors (including alcohol, viruses, diet, blood loss). Iron overload without hemochromatosis is characterized by high levels of serum ferritin and normal TS, as seen in dysmetabolic hepatosiderosis. Elevated serum ferritin levels predict incident type 2 diabetes in prospective studies and have been associated with hypertension, dyslipidemia, glucose tolerance disturbances, central adiposity, and metabolic syndrome. High ferritin levels are not synonymous with iron overload and may in some cases be a simple marker of insulin resistance.
 ...
PMID:[Iron overload and insulin resistance]. 1629 93

Genetic variation in alpha-adducin cytoskeletal protein is implicated in the polymerization and bundling of actin and alteration of the Na/K pump, resulting in abnormal renal sodium transport and hypertension in Milan hypertensive rats and humans. To investigate the molecular involvement of alpha-adducin in controlling Na/K pump activity, wild-type or mutated rat and human alpha-adducin forms were, respectively, transfected into several renal cell lines. Through multiple experimental approaches (microscopy, enzymatic assays, coimmunoprecipitation), we showed that rat and human mutated forms increased Na/K pump activity and the number of pump units; moreover, both variants coimmunoprecipitate with Na/K pump. The increased Na/K pump activity was not due to changes in its basolateral localization, but to an alteration of Na/K pump residential time on the plasma membrane. Indeed, both rat and human mutated variants reduced constitutive Na/K pump endocytosis and similarly affected transferrin receptor trafficking and fluid-phase endocytosis. In fact, alpha-adducin was detected in clathrin-coated vesicles and coimmunoprecipitated with clathrin. These results indicate that adducin, besides its modulatory effects on actin cytoskeleton dynamics, might play a direct role in clathrin-dependent endocytosis. The constitutive reduction of the Na/K pump endocytic rate induced by mutated adducin variants may be relevant in Na-dependent hypertension.
 ...
PMID:alpha-Adducin mutations increase Na/K pump activity in renal cells by affecting constitutive endocytosis: implications for tubular Na reabsorption. 1852 56

Hypertension provokes differential trafficking of the renal proximal tubule Na(+)/H(+) exchanger 3 (NHE3) to the base of the apical microvilli and Na(+)-P(i) cotransporter 2 (NaPi2) to endosomes. The resultant diuresis and natriuresis are key to blood pressure control. We tested the hypothesis that this differential trafficking of NHE3 vs. NaPi2 was associated with partitioning to distinct membrane domains. In anesthetized rats, arterial pressure was increased (104 +/- 2 to 142 +/- 4 mmHg, 15 min) by arterial constriction and urine output increased 23-fold. Renal membranes were fractionated by cold 1% Triton X-100 extraction then centrifugation through OptiPrep flotation gradients. In controls, 84 +/- 9% of NHE3 localized to flotillin-enriched lipid raft domains and 69 +/- 5% of NaPi2 localized to transferrin receptor-enriched nonrafts. MyosinVI and dipeptidyl peptidase IV, associated with NHE3 regulation, coenriched in lipid rafts with NHE3, while NHE regulatory factor-1 coenriched in nonrafts with NaPi2. Partitioning was not altered by hypertension. Detergent insoluble membranes were pelleted after detergent extraction. NHE3 detergent insolubility decreased as it redistributed from body (80 +/- 10% detergent insoluble) to base (75 +/- 3%) of the apical microvilli, while NaPi2 partitioned into more insoluble domains as it moved from the microvilli (45 +/- 7% detergent insoluble) to endosomes (82 +/- 1%). In conclusion, NHE3 and NaPi2, while both localized to apical microvilli, are segregated into domains: NHE3 to lipid rafts and NaPi2 to nonrafts. These domain properties may play a role in the distinct trafficking patterns observed during elevated pressures: NHE3 remains in rafts and settles to the base of the microvilli while NaPi2 is freely endocytosed.
 ...
PMID:Renal NHE3 and NaPi2 partition into distinct membrane domains. 1915 99

Iron accumulation is associated with the pathogenesis of several cardiovascular diseases. However, the preventive effects of iron restriction (IR) against cardiovascular disease remain obscure. We investigated the effects of dietary IR on cardiovascular pathophysiology and the involved mechanism in Dahl salt-sensitive rats. Dahl salt-sensitive rats were provided either a normal or high-salt (HS) diet. Another subset of Dahl salt-sensitive rats were fed an HS with iron-restricted (HS+IR) diet for 11 weeks. Dahl salt-sensitive rats given an HS diet developed hypertension, heart failure, and decreased a survival rate after 11 weeks on the diet. In contrast, IR attenuated the development of hypertension and heart failure, thereby improving survival rate. Dietary IR suppressed cardiovascular hypertrophy, fibrosis, and inflammation in HS rats. The phosphorylation of Akt, AMP-activated protein kinase, and endothelial nitric oxide synthase was decreased in the aorta of HS rats, whereas they were ameliorated by the IR diet. Aortic expression of the cellular iron import protein transferrin receptor 1, and the iron storage protein ferritin H-subunit, was upregulated in HS rats. IR also attenuated proteinuria and increased oxidative stress in the HS group. N(G)-nitro-L-arginine methyl ester abolished the beneficial effects of IR and decreased survival rate in HS+IR rats. Dietary IR had protective effects on salt-induced hypertension, cardiovascular remodeling, and proteinuria through the inhibition of oxidative stress, and maintenance of Akt, AMP-activated protein kinase, and endothelial nitric oxide synthase in the aorta. IR could be an effective strategy for prevention of HS-induced organ damage in salt-sensitive hypertensive patients.
Hypertension 2011 Mar
PMID:Dietary iron restriction prevents hypertensive cardiovascular remodeling in Dahl salt-sensitive rats. 2126 29

Iron homeostasis influences the development of pulmonary arterial hypertension (PAH) associated with hypoxia or hematologic disorders. To investigate whether severity of idiopathic PAH (IPAH) is impacted by alterations in iron metabolism, we assessed iron metabolic markers, including levels of zinc-protoporphyrin (Zn-pp), transferrin receptor, and red blood cell numbers and morphology in IPAH, associated PAH and sleep apnea-induced pulmonary hypertension patients in comparison to healthy controls and asthmatics. Despite similarly normal measures of iron metabolism, Zn-pp levels in IPAH and sleep apnea patients were elevated approximately twofold, indicating deficient iron incorporation to form heme and levels were closely related to measures of disease severity. Consistent with high Zn-pp, PAH patients had increased red cell distribution width (RDW). In an expanded cohort including patients with IPAH and familial disease, the RDW was validated and related to clinical parameters of severity; including pulmonary artery pressures and 6-minute walk distances. These results reveal an increased prevalence of subclinical functional iron deficiency in primary forms of PAH that is quantitatively related to disease severity. This suggests that altered iron homeostasis influences disease progression and demonstrates the importance of closely monitoring iron status in PAH patients.
 ...
PMID:High levels of zinc-protoporphyrin identify iron metabolic abnormalities in pulmonary arterial hypertension. 2188 11


1 2 3 Next >>