Rapid changes in cardiac myofilament function following the acute activation of estrogen receptor alpha
Estrogens alter heart contractility through changes in myofilament function. Studies have focused on chronic estrogen exposure, while mechanisms of non-genomic estrogen pathways are not understood. Moreover, the effects of selective estrogen receptor (ER) isoform activation are not known. This thesis sought to determine how acute activation of ER[alpha] impacts cardiac myofilaments and the intracellular mechanisms of action. I found that the activation of ER[alpha] depresses actomyosin MgATPase activity and decreases the Ca2+ sensitivity of cardiac myofilaments. Studies have implicated p38 MAPK in non-genomic estrogen signalling. Inhibition of p38 attenuates the functional changes observed, whereas PKC, PKA or PI3K antagonism does not alter the myofilament effects of ER[alpha] activation. Interestingly, ER[alpha] stimulation does not affect total phosphorylation of myofilament proteins, but does alter troponin I phosphorylation at serines 23/24. This study provides novel evidence supporting rapid, non-genomic changes in cardiac myofilament function following ER[alpha] stimulation, mediated by the p38 MAPK pathway.