RESUMEN
Plasminogen activator inhibitor-1 (PAI-1), an endogenous inhibitor of a major fibrinolytic factor, tissue-type plasminogen activator, can both promote and inhibit angiogenesis. However, the physiologic role and the precise mechanisms underlying the angiogenic effects of PAI-1 remain unclear. In the present study, we report that pharmacologic inhibition of PAI-1 promoted angiogenesis and prevented tissue necrosis in a mouse model of hind-limb ischemia. Improved tissue regeneration was due to an expansion of circulating and tissue-resident granulocyte-1 marker (Gr-1(+)) neutrophils and to increased release of the angiogenic factor VEGF-A, the hematopoietic growth factor kit ligand, and G-CSF. Immunohistochemical analysis indicated increased amounts of fibroblast growth factor-2 (FGF-2) in ischemic gastrocnemius muscle tissues of PAI-1 inhibitor-treated animals. Ab neutralization and genetic knockout studies indicated that both the improved tissue regeneration and the increase in circulating and ischemic tissue-resident Gr-1(+) neutrophils depended on the activation of tissue-type plasminogen activator and matrix metalloproteinase-9 and on VEGF-A and FGF-2. These results suggest that pharmacologic PAI-1 inhibition activates the proangiogenic FGF-2 and VEGF-A pathways, which orchestrates neutrophil-driven angiogenesis and induces cell-driven revascularization and is therefore a potential therapy for ischemic diseases.
Asunto(s)
Inductores de la Angiogénesis/metabolismo , Neovascularización Fisiológica/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Piperazinas/farmacología , Regeneración/efectos de los fármacos , Serpina E2/antagonistas & inhibidores , para-Aminobenzoatos , Ácido 4-Aminobenzoico/farmacología , Animales , Células Cultivadas , Evaluación Preclínica de Medicamentos , Fibrinolíticos/farmacología , Humanos , Metaloproteinasa 9 de la Matriz/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neutrófilos/inmunología , Neutrófilos/metabolismo , Neutrófilos/fisiología , Regeneración/fisiología , Activador de Tejido Plasminógeno/genética , Regulación hacia Arriba/efectos de los fármacosRESUMEN
A 70-year-old woman under anticonvulsive therapy with carbamazepine and valproate was diagnosed as polymyalgia rheumatica. She responded to the prednisolone therapy so poorly that she required high dose prednisolone and methotrexate, and it was difficult to reduce prednisolone. After discontinuing of carbamazepine, her steroid response improved immediately. Carbamazepine is known to induce hepatic enzyme CYP3A4 and alter metabolism of other drugs. In our case, the effect of prednisolone might have been reduced by carbamazepine. This case suggests more attention should be paid to the interaction between carbamazepine and prednisolone.