Activation of the Amino Acid Response Pathway Blunts the Effects of Cardiac Stress.
Activation of the Amino Acid Response Pathway Blunts the Effects of Cardiac Stress.
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DOI：
10.1161/jaha.116.004453
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发表时间：
2017-05-09
影响因子：
5.4
通讯作者：
Willette RN
中科院分区：
文献类型：
--
作者：
Qin P;Arabacilar P;Bernard RE;Bao W;Olzinski AR;Guo Y;Lal H;Eisennagel SH;Platchek MC;Xie W;Del Rosario J;Nayal M;Lu Q;Roethke T;Schnackenberg CG;Wright F;Quaile MP;Halsey WS;Hughes AM;Sathe GM;Livi GP;Kirkpatrick RB;Qu XA;Rajpal DK;Faelth Savitski M;Bantscheff M;Joberty G;Bergamini G;Force TL;Gatto GJ Jr;Hu E;Willette RN
氨基酸反应(AAR)是一种进化上保守的保护性机制，由氨基酸缺乏激活，通过一个关键的控制不可降压的2。除了动员氨基酸，AAR还广泛地影响多种途径的基因和蛋白质的表达，并引起抗纤维化、自噬和抗炎活性。然而，关于它在心脏应激中的作用，人们知之甚少。我们的目的是研究Prolyl-tRNA合成酶抑制剂常青藤酮对心脏成纤维细胞、心肌细胞以及心脏应激和衰竭小鼠模型中AAR途径的影响。与其抑制Prolyl-tRNA合成酶的能力一致，常青酮诱导了心脏成纤维细胞AAR途径的普遍控制、不可撤销的2依赖的激活，这一点体现在已知的AAR靶基因的激活、转录组和蛋白质组的广泛调控以及L-Pro的逆转。在血管紧张素II/苯肾上腺素、横断性主动脉收缩和急性缺血再灌注损伤3种心脏应激模型上观察了大黄酮的作用。它激活了心脏中的AAR途径，改善了存活率、肺充血、左室重构/纤维化和左心功能，并挽救了缺血心肌。在人心脏成纤维细胞中，常青藤酮以一种非可逆的2依赖方式显著减少胶原沉积，并抑制细胞外基质蛋白质组。在人诱导的多能干细胞来源的心肌细胞中，常山酮以一种一般对照的不可降压的2/eIF2α依赖的方式阻断了与内皮素-1介导的病理性肥大激活相关的基因表达，并恢复了自噬。常青藤酮激活心脏中的AAR途径，减弱心脏应激的结构和功能效应。
The amino acid response (AAR) is an evolutionarily conserved protective mechanism activated by amino acid deficiency through a key kinase, general control nonderepressible 2. In addition to mobilizing amino acids, the AAR broadly affects gene and protein expression in a variety of pathways and elicits antifibrotic, autophagic, and anti‐inflammatory activities. However, little is known regarding its role in cardiac stress. Our aim was to investigate the effects of halofuginone, a prolyl‐tRNA synthetase inhibitor, on the AAR pathway in cardiac fibroblasts, cardiomyocytes, and in mouse models of cardiac stress and failure. Consistent with its ability to inhibit prolyl‐tRNA synthetase, halofuginone elicited a general control nonderepressible 2–dependent activation of the AAR pathway in cardiac fibroblasts as evidenced by activation of known AAR target genes, broad regulation of the transcriptome and proteome, and reversal by l‐proline supplementation. Halofuginone was examined in 3 mouse models of cardiac stress: angiotensin II/phenylephrine, transverse aortic constriction, and acute ischemia reperfusion injury. It activated the AAR pathway in the heart, improved survival, pulmonary congestion, left ventricle remodeling/fibrosis, and left ventricular function, and rescued ischemic myocardium. In human cardiac fibroblasts, halofuginone profoundly reduced collagen deposition in a general control nonderepressible 2–dependent manner and suppressed the extracellular matrix proteome. In human induced pluripotent stem cell–derived cardiomyocytes, halofuginone blocked gene expression associated with endothelin‐1‐mediated activation of pathologic hypertrophy and restored autophagy in a general control nonderepressible 2/eIF2α‐dependent manner. Halofuginone activated the AAR pathway in the heart and attenuated the structural and functional effects of cardiac stress.