Meyer-Kirchrath Jutta, Martin Melanie, Schooss Christina, Jacoby Christoph, Flögel Ulrich, Marzoll Andrea, Fischer Jens W, Schrader Jürgen, Schrör Karsten, Hohlfeld Thomas
Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum, Heinrich-Heine-Universität, Moorenstr. 5, D-40225 Düsseldorf, Germany.
Cardiovasc Res. 2009 Feb 1;81(2):310-8. doi: 10.1093/cvr/cvn312. Epub 2008 Nov 18.
Prostaglandin E(2) (PGE(2)) has been shown to mediate anti-ischaemic effects and cardiomyocyte hypertrophy and there is evidence for an involvement of the prostaglandin EP(3)-receptor subtype. This study focuses on the EP(3)-mediated hypertrophic action and investigates intracellular signalling pathways of the EP(3)-receptor subtype in the murine heart.
Cardiac function was analyzed in vivo by magnetic resonance imaging (MRI) in transgenic (tg) mice with cardio-specific overexpression of the EP(3) receptor in comparison with wild-type (wt) mice. Left ventricular (LV) function was determined in isolated perfused hearts subjected to 60 min of zero-flow ischaemia and 45 min of reperfusion. Calcineurin activity and nuclear activity of nuclear factor of activated T-cells (NFAT) were determined by a modified malachite green assay and ELISA, respectively. Extracellular matrix compounds were analyzed by RT-PCR and histology. MRI indicated a significant increase in end-diastolic and end-systolic volume in tg hearts. LV ejection fraction was severely decreased in tg hearts while the relative LV mass was significantly increased. In Langendorff perfused hearts, EP(3)-receptor overexpression resulted in a marked blunting of the ischaemia-induced increase in LV end-diastolic pressure and creatine kinase release. Analysis of EP(3)-receptor-mediated signalling revealed significantly increased calcineurin activity and nuclear activity of NFAT in tg hearts. Moreover, elevated mRNA levels of collagen types I and III as well as the collagen-binding proteoglycans biglycan and decorin were detected in tg hearts.
EP(3)-receptor-mediated signalling results in a significant anti-ischaemic action and activation of the pro-hypertrophic calcineurin signalling pathway, suggesting the involvement of the EP(3) subtype in both PGE(2)-mediated cardioprotection as well as cardiac hypertrophy.
前列腺素E₂（PGE₂）已被证明可介导抗缺血作用和心肌细胞肥大，且有证据表明前列腺素EP₃受体亚型参与其中。本研究聚焦于EP₃介导的肥大作用，并研究小鼠心脏中EP₃受体亚型的细胞内信号通路。
通过磁共振成像（MRI）在体内分析转基因（tg）小鼠心脏特异性过表达EP₃受体与野生型（wt）小鼠相比的心脏功能。在经历60分钟零流量缺血和45分钟再灌注的离体灌注心脏中测定左心室（LV）功能。分别通过改良孔雀石绿测定法和酶联免疫吸附测定法测定钙调神经磷酸酶活性和活化T细胞核因子（NFAT）的核活性。通过逆转录聚合酶链反应（RT-PCR）和组织学分析细胞外基质成分。MRI显示tg心脏的舒张末期和收缩末期容积显著增加。tg心脏的左心室射血分数严重降低，而左心室相对质量显著增加。在Langendorff灌注心脏中，EP₃受体过表达导致缺血诱导的左心室舒张末期压力升高和肌酸激酶释放明显减弱。对EP₃受体介导的信号传导分析显示，tg心脏中钙调神经磷酸酶活性和NFAT核活性显著增加。此外，在tg心脏中检测到I型和III型胶原蛋白以及胶原蛋白结合蛋白聚糖双糖链蛋白聚糖和核心蛋白聚糖的mRNA水平升高。
EP₃受体介导的信号传导导致显著的抗缺血作用以及促肥大钙调神经磷酸酶信号通路的激活，提示EP₃亚型参与PGE₂介导的心脏保护以及心脏肥大。
