Tese de doutoramento, Bioquímica (Bioquímica Clínica), Universidade de Lisboa, Faculdade de Ciências, 2013The cellular responses to steroids are mediated by two general mechanisms: genomic and rapid/nongenomic effects. Identification of the mechanisms underlying aldosterone’s rapid versus their genomic actions have been difficult to study and are not clearly understood. I explored the hypothesis that striatin is a critical intermediary of the rapid/nongenomic effects of aldosterone and that striatin serves as a novel link between the actions of the mineralocorticoid and estrogen receptors. In human and mouse endothelial cells, aldosterone promoted an increase in pERK that peaked at 15 minutes. Striatin is a critical mediator in this process as reducing striatin levels with siRNA technology prevented the rise in pERK levels. In contrast, reducing striatin did not significantly affect two well-characterized genomic responses to aldosterone. Down regulation of striatin with siRNA produced similar effects on estrogen’s actions – reducing nongenomic, but not the genomic actions investigated. Aldosterone, but not estrogen, increased striatin levels. When endothelial cells were pre-treated with aldosterone, the rapid/nongenomic response to estrogen on peNOS/eNOS ratio was enhanced and accelerated significantly. Importantly, pretreatment with estrogen did not enhance aldosterone’s nongenomic response on pERK. In conclusion, these results indicate that striatin is a novel mediator for both aldosterone’s and estrogen’s rapid and nongenomic mechanisms of action on pERK and peNOS, respectively, thereby providing evidence for a synergistic effect between the mineralocorticoid receptor and the estrogen receptor. Furthermore, these results suggest a unique level of interactions between steroids on the cardiovascular system that may have broad application for the treatment of cardiovascular diseases.Fundação para a Ciência e a Tecnologia (FCT, SFRH /BD/28601/2006 - POPH (QREN) - Formação Avançada), comparticipação do FSE e do MCTES e de subsídios do NHLBI/NIH USA: R01HL090632, R01HL094452 e R01HL09651
