Activin A impairs insulin action in cardiomyocytes via up-regulation of miR-143
Activin A impairs insulin action in cardiomyocytes via up-regulation of miR-143
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DOI：
10.1093/cvr/cvt173
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发表时间：
2013-11-01
影响因子：
10.8
通讯作者：
Ouwens, D. Margriet
中科院分区：
文献类型：
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作者：
Blumensatt, Marcel;Greulich, Sabrina;Ouwens, D. Margriet
增强的激活素A从心外膜脂肪组织（EAT）释放与2型糖尿病（T2D）中心脏功能障碍的发展有关。这项研究检查了心外膜脂肪因子在心肌细胞中诱导的胰岛素作用的抑制是否可以归因于miRNA表达的改变。通过实时PCR在原发性成人大鼠心脏肌细胞（ARC）中通过实时PCR评估了miRNA水平有和没有T2D的患者的活检（CM-EAT）。 CM-EAT-T2D从没有T2D的患者中改变了ARC与CM-EAT的八个miRNA的表达。其中，只有miR-143/145簇的表达受激活素A的影响与CM-EAT-T2D相同的方向。因此，激活素A中和抗体阻止了CM-EAT-T2D诱导miR-143/145簇。随后，研究了miR-143/145簇对胰岛素作用的影响。将HL-1细胞用前体MIR-143（MIR-143前）转染，但不是MIR-145，它钝化了Akt及其底物脯氨酸富含Akt的胰岛素介导的磷酸化40 kDa（PRAS40） ，并减少胰岛素刺激的葡萄糖摄取。慢病毒介导的MIR-143在ARC中的表达降低了胰岛素诱导的Akt磷酸化。这些作用归因于miR-143靶标和胰岛素作用的调节剂，氧蛋白酶结合蛋白相关的蛋白8（ORP8）在ARC和HL-1细胞中的调节。最后，LNA-ANTI-MIR-143免受CM-EAT-T2D对ARC的胰岛素作用的有害作用。活性A释放从EAT-T2D释放出来，通过在心肌细胞中诱导miR-143诱导MiR-143抑制胰岛素作用。该miRNA通过对新型胰岛素作用调节剂ORP8的下调抑制AKT途径。
Enhanced activin A release from epicardial adipose tissue (EAT) has been linked to the development of cardiac dysfunction in type 2 diabetes (T2D). This study examined whether the inhibition of insulin action induced by epicardial adipokines in cardiomyocytes can be ascribed to alterations in miRNA expression.Expression levels of miRNAs were assessed by real-time PCR in primary adult rat cardiomyocytes (ARC) exposed to conditioned media generated from EAT biopsies (CM-EAT) from patients with and without T2D. CM-EAT-T2D altered the expression of eight miRNAs in ARC vs. CM-EAT from patients without T2D. Of these, only expression of the miR-143/145 cluster was affected by activin A in the same direction as CM-EAT-T2D. Accordingly, activin A neutralizing antibodies prevented the induction of the miR-143/145 cluster by CM-EAT-T2D. Subsequently, the impact of the miR-143/145 cluster on insulin action was investigated. Transfection of HL-1 cells with precursor-miR-143 (pre-miR-143), but not pre-miR-145, blunted the insulin-mediated phosphorylation of Akt and its substrate proline-rich Akt substrate of 40 kDa (PRAS40), and reduced insulin-stimulated glucose uptake. Also lentivirus-mediated expression of pre-miR-143 in ARC reduced insulin-induced Akt phosphorylation. These effects were ascribed to down-regulation of the miR-143 target and regulator of insulin action, the oxysterol-binding protein-related protein 8 (ORP8) in both ARC and HL-1 cells. Finally, LNA-anti-miR-143 protected against the detrimental effects of CM-EAT-T2D on insulin action in ARC.Activin A released from EAT-T2D inhibits insulin action via the induction of miR-143 in cardiomyocytes. This miRNA inhibits the Akt pathway through down-regulation of the novel regulator of insulin action, ORP8.