Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0032463 (polycythemia vera)
 3,374 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The renal blood flow (RBF) of patients with polycythemia rubra vera is increased despite the high hematocrit (Hct) which elevates the whole blood viscosity. Since blood viscosity determines the shear force on the endothelium which is a major stimulus to nitric oxide (NO) release, we investigated the hypothesis that renal vasodilation during erythropoietin-induced erythrocytosis is mediated by the L-arginine-NO pathway. Groups of Sprague-Dawley rats received thrice weekly injections of erythropoietin (E) for two to five weeks; responses were contrasted with normal rats (N) which received sham injections. The first group was studied after five weeks of erythropoietin injections which led to sharp increases in Hct (E: 72 +/- 3 vs. N: 44 +/- 1%) and mean arterial pressure (MAP: 126 +/- 3 vs. 107 +/- 3 mm Hg). These rats had an elevated basal RBF whether measured by the clearance and renal extraction of PAH or by a transit-time renal blood flow meter. Subsequent groups were studied after two to three weeks of erythropoietin which raised the Hct more modestly to 59 +/- 2%. In this group, the basal MAP was similar in E and N rats. Graded doses of the NO synthase inhibitor, N omega-monomethyl-L-arginine (L-NMA) led to a steeper rise in MAP in E than N; at the highest doses, the MAP had increased by 36 +/- 2 in E and 23 +/- 3 mm Hg in N (P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Nitric oxide mediates renal vasodilation during erythropoietin-induced polycythemia. 837 85

Polycythemia vera (PV) is a clonal myeloproliferative disorder characterized by excessive erythrocyte production. Most patients with PV harbor an activating JAK2 mutation, but the molecular links between this mutation and erythrocyte overproduction are unknown. The interaction between death receptors and their ligands contributes to the physiological regulation of erythropoiesis through the inhibition of erythroblast proliferation and differentiation. With the use of an in vitro culture system to generate differentiating erythroid cells, we found that erythroblasts derived from patients with PV harboring the JAK2 V617F mutation were able to proliferate and generate higher numbers of mature erythroid cells in the presence of inhibitory signals delivered by CD95 (Fas/Apo-1) and TRAIL receptor stimulation. JAK2-mutated PV erythroblasts showed lower levels of CD95-induced caspase activation and incomplete caspase-mediated cleavage of the erythroid transcription factor GATA-1, which was entirely degraded in normal erythroblasts on CD95 stimulation. JAK2 mutation was associated in PV erythroblasts with cytokine-independent activation of the JAK2 effectors Akt/PKB and ERK/MAP and with a deregulated expression of c-FLIP(short), a potent cellular inhibitor of death receptor-induced apoptosis. These results show the presence in PV erythroblasts of proliferative and antiapoptotic signals that may link the JAK2 V617F mutation with the inhibition of death receptor signaling, possibly contributing to a deregulation of erythropoiesis.
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PMID:Increased death receptor resistance and FLIPshort expression in polycythemia vera erythroid precursor cells. 1638 30