Cardiovascular Research Group, Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada.
PLoS One. 2012;7(7):e41076. doi: 10.1371/journal.pone.0041076. Epub 2012 Jul 30.
Estrogens have well-recognized and complex cardiovascular effects, including altering myocardial contractility through changes in myofilament function. The presence of multiple estrogen receptor (ER) isoforms in the heart may explain some discrepant findings about the cardiac effects of estrogens. Most studies examining the impact of estrogens on the heart have focused on chronic changes in estrogen levels, and have not investigated rapid, non-genomic pathways. The first objective of this study was to determine how acute activation of ERα impacts cardiac myofilaments. Nongenomic myocardial estrogen signaling is associated with the activation of a variety of signaling pathways. p38 MAPK has been implicated in acute ER signaling in the heart, and is known to affect myofilament function. Thus, the second objective of this study was to determine if acute ERα activation mediates its myofilament effects through p38 MAPK recruitment. Hearts from female C57Bl/6 mice were perfused with the ERα agonist PPT and myofilaments isolated. Activation of ERα depressed actomyosin MgATPase activity and decreased myofilament calcium sensitivity. Inhibition of p38 MAPK attenuated the myofilament effects of ERα activation. ERα stimulation did not affect global myofilament protein phosphorylation, but troponin I phosphorylation at the putative PKA phosphorylation sites was decreased. Changes in myofilament activation did not translate into alterations in whole heart function. The present study provides evidence supporting rapid, non-genomic changes in cardiac myofilament function following acute ERα stimulation mediated by the p38 MAPK pathway.
雌激素对心血管系统具有广泛而复杂的作用，包括通过改变肌丝功能来改变心肌收缩力。心脏中存在多种雌激素受体 (ER) 同工型，这可能解释了雌激素对心脏作用的一些不一致发现。大多数研究雌激素对心脏影响的研究都集中在雌激素水平的慢性变化上，而没有研究快速的非基因组途径。本研究的首要目标是确定 ERα 的急性激活如何影响心肌肌丝。非基因组心肌雌激素信号与多种信号通路的激活有关。p38 MAPK 已被牵连到心脏中 ER 的急性信号转导中，并且已知其会影响肌丝功能。因此，本研究的第二个目标是确定 ERα 激活是否通过 p38 MAPK 募集来介导其肌丝效应。用 ERα 激动剂 PPT 灌注雌性 C57Bl/6 小鼠的心脏并分离肌丝。ERα 的激活抑制肌球蛋白 MgATP 酶活性并降低肌丝钙敏感性。p38 MAPK 的抑制减弱了 ERα 激活对肌丝的影响。ERα 刺激不会影响肌丝蛋白的整体磷酸化，但肌钙蛋白 I 在假定的 PKA 磷酸化位点的磷酸化减少。肌丝激活的变化并没有转化为整个心脏功能的改变。本研究提供的证据支持 p38 MAPK 途径介导的急性 ERα 刺激后心脏肌丝功能的快速非基因组变化。
