Cardiomyocyte-expressed farnesoid-X-receptor is a novel apoptosis mediator and contributes to myocardial ischaemia/reperfusion injury
Cardiomyocyte-expressed farnesoid-X-receptor is a novel apoptosis mediator and contributes to myocardial ischaemia/reperfusion injury
复制标题
心肌细胞表达的法尼醇-X-受体是一种新型凋亡介质，有助于心肌缺血/再灌注损伤
DOI：
10.1093/eurheartj/ehs011
复制
发表时间：
2013-06-01
影响因子：
39.3
通讯作者：
He, Ben
中科院分区：
文献类型：
--
作者：
Pu, Jun;Yuan, Ancai;He, Ben
目的 新出现的证据表明核受体在心血管生理学/病理学中发挥着关键的调节作用。最近，代谢核受体超家族的一员法尼醇X受体（FXR）已被证明在血管细胞中表达，在血管生理/病理学中发挥重要作用。然而，FXR 的潜在心脏功能仍不清楚。我们研究了FXR在心脏中的表达和生物学功能。方法和结果在分离的新生大鼠心肌细胞和成纤维细胞中均检测到Farnesoid-X-受体。天然和合成的 FXR 激动剂上调心脏 FXR 表达，刺激心肌细胞凋亡，并呈剂量和时间依赖性降低心肌细胞活力。机制研究表明，FXR 激动剂会破坏线粒体，其特征是线粒体通透性转换孔激活、线粒体电位耗散、细胞色素 c 释放以及 caspase-9 和 -3 激活。这种线粒体凋亡反应可以通过 siRNA 介导的内源 FXR 沉默或线粒体死亡信号传导的药理抑制来消除。此外，在成年小鼠心脏中检测到低水平的 FXR，在心肌缺血/再灌注 (MI/R) 后显着上调（接近 2.0 倍）。 FXR的药物抑制或基因消融显着减少心肌细胞凋亡29.0-53.4，减少梗死面积23.4-49.7，并改善缺血/再灌注心肌的心功能。结论这些结果表明核受体FXR作为心脏组织中的新型功能性受体，调节心肌细胞凋亡，并有助于MI/R损伤。
Aims Emerging evidence indicates that nuclear receptors play a critical regulatory role in cardiovascular physiology/pathology. Recently, farnesoid-X-receptor (FXR), a member of the metabolic nuclear receptor superfamily, has been demonstrated to be expressed in vascular cells, with important roles in vascular physiology/pathology. However, the potential cardiac function of FXR remains unclear. We investigated the cardiac expression and biological function of FXR.Methods and results Farnesoid-X-receptor was detected in both isolated neonatal rat cardiac myocytes and fibroblasts. Natural and synthetic FXR agonists upregulated cardiac FXR expression, stimulated myocyte apoptosis, and reduced myocyte viability dose- and time-dependently. Mechanistic studies demonstrated that FXR agonists disrupted mitochondria, characterized by mitochondrial permeability transition pores activation, mitochondrial potential dissipation, cytochrome c release, and both caspase-9 and -3 activation. Such mitochondrial apoptotic responses were abolished by siRNA-mediated silencing of endogenous FXR or pharmacological inhibition of mitochondrial death signalling. Furthermore, low levels of FXR were detected in the adult mouse heart, with significant (similar to 2.0-fold) upregulation after myocardial ischaemia/reperfusion (MI/R). Pharmacological inhibition or genetic ablation of FXR significantly reduced myocardial apoptosis by 29.0-53.4, decreased infarct size by 23.4-49.7, and improved cardiac function in ischaemic/reperfused myocardium.Conclusion These results demonstrate that nuclear receptor FXR acts as a novel functional receptor in cardiac tissue, regulates apoptosis in cardiomyocytes, and contributes to MI/R injury.