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La prostaciclina derivada de la ciclooxigenasa-2 regula la formación de trombos arteriales al suprimir el factor de
Silvia S Barbieri1, Patrizia Amadio, Sara Gianellini
1Centro Cardiologico Monzino, IRCCS, Via Parea 4, 20138 Milano, Italy. silviabarbieri@yahoo.com
Circulation
|August 7, 2012
Resumen
Los inhibidores selectivos de la ciclooxigenasa-2 (COX-2) aumentan los riesgos trombóticos. La deleción de COX-2 mejora la formación de trombos al reducir la prostaciclina y la sirtuina-1 (SIRT1), aumentando el factor de tejido (TF).
Área de la Ciencia:
- Biología Cardiovascular Biología Cardiovascular
- Investigación de la trombosis.
- Farmacología Farmacología.
Sus antecedentes:
- Los inhibidores selectivos de la ciclooxigenasa-2 (COX-2) están relacionados con un aumento del infarto de miocardio y eventos trombóticos.
- Los mecanismos precisos que subyacen a estos riesgos trombóticos aún no se comprenden por completo.
Objetivo del estudio:
- Para dilucidar los mecanismos por los cuales la COX-2 influye en la formación de trombos arteriales.
- Para investigar el papel de la prostaciclina, el receptor-δ activado por el proliferador peroxisomático (PPARδ) y la sirtuina-1 (SIRT1) en la trombosis mediada por COX-2.
Principales métodos:
- Comparación de la formación de trombos arteriales inducidos por cloruro férrico en ratones con knockout COX-2 y ratones de tipo salvaje.
- Experimentos de transfusión cruzada para evaluar las contribuciones plaquetarias.
- Análisis de la expresión y actividad de la prostaciclina sintasa, el receptor-δ activado por el proliferador peroxisomático, la sirtuina-1 (SIRT1) y el factor tisular (TF).
- Modulación farmacológica de las vías de la prostaciclina y PPARδ, y inhibición/activación de SIRT1.
Principales resultados:
- Los ratones knockout de COX-2 exhibieron una formación de trombo arterial significativamente mayor en comparación con los ratones de tipo salvaje.
- La deleción de COX-2 condujo a una disminución de la prostaciclina y la expresión de SIRT1, con un consiguiente aumento en la iniciación de la coagulación por el factor tisular (TF).
- El agonismo de la prostaciclina o PPARδ invirtió el fenotipo protrombótico en ratones con knockout COX-2, mientras que su antagonismo en ratones de tipo salvaje promovió la trombosis.
- La inhibición de SIRT1 aumentó la actividad de TF y la formación de trombos, mientras que la activación de SIRT1 redujo la actividad de TF y el estado protrombótico en ratones knockout de COX-2.
Conclusiones:
- La vía de la prostaciclina/PPARδ modula SIRT1 y TF, lo que representa un nuevo mecanismo que controla la formación de trombos arteriales.
- Dirigirse a SIRT1 y TF a través de estas vías puede ofrecer estrategias terapéuticas para las complicaciones aterotrombóticas asociadas con los inhibidores de la COX-2.
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