Mecanismo molecllar de las estatinas en el tratmiento de la eritrocitosis patoológica de altura

Introduccion La Eritrocitosis Patologica de Altura es la manifestacion hematologica de la Enfermedad Cronica de Altura, por adaptacion inadecuada a grandes alturas de genes reguladores de la eritropoyesis. Las estatinas son inhibidores de la via del mevalonato involucrado en la regulacion de la eritropoyesis. El presente trabajo describe los mecanismos moleculares de la inhibicion de la eritropoyesis en pacientes con eritrocitosis patologicas. Material y metodos Se estudiaron 35 pacientes con eritrocitosis patologicas con radicatorias en las ciudades de La Paz y El Alto (3600 y 4000 msnm respectivamente). Se realizaron Cultivo de celulas progenitoras hematopoyeticas y Western Blot. Resultados Statins induce apoptosis of erythroid progenitors in the cell culture medium. Without the supplement of simvastatin the apoptosis was 12.3% and With simvastatin the apoptosis was 38.4% (p = 0.001). Furthermore statins inhibit the proliferation and differentiation of erythroid progenitors. Conclusiones Los mecanismos moleculares involucrados en la inhibicion de la eritropoyesis son: a) Bloqueo de la isoprenilacion de Rho y Ras, b) Inhibicion de la fosforilacion de Jak-2 y Stat-5, c) inhibicion de la glicosilacion del EpoR, d) Disminucion de colesterol en microdominios de la membrana celular (raft lipid), e) Induccion de apoptosis a traves de BCLxL y caspasa 9.(AU) Introduction The High altitude Pathological Erythrocytosis is the chronic mountain sickness hematologic manifestation by inadequate adaptation to high altitudes of genes regulating erythropoiesis. Statins are inhibitors of the mevalonate pathway involved in the regulation of erythropoiesis. This paper describes the molecular mechanisms of erythropoiesis inhibitionin patients with pathological erythrocytosis. Material and methods We studied 35 patients with pathological erythrocytosis from La Paz and El Alto city (3600 and 4000 masl respectively). Were performed hematopoietic progenitor cell culture and Western blotting. Results Statins induce apoptosis in liquid culture medium. without simvastatin erythroid progenitors from apoptosis presentaron and 12.3% in the group supplemented with simvastatin 38.4% apoptosis (p = 0.001), statins also inhibit the proliferation and differentiation of erythroid progenitors, and inhibit transcription of STAT-5. Conclusions The molecular mechanisms involved in the erythropoiesis inhibition are: a) Inhibition of Ras and Rho isoprenylation, b) Inhibition of Jak-2 and Stat-5 phosphorylation, c) inhibition of EpoR glycosylation, d) Statins reduce lipid rafts cholesterol and reduce JAK2 localization to lipid rafts, e) Induction of apoptosis through caspase 9 and BclxL.(AU)