Activation of the Amino Acid Response Pathway Blunts the Effects of Cardiac Stress.
BACKGROUND
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.


METHODS AND RESULTS
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.


CONCLUSIONS
Halofuginone activated the AAR pathway in the heart and attenuated the structural and functional effects of cardiac stress.
['Qin|Pu|P|', 'Arabacilar|Pelin|P|', 'Bernard|Roberta E|RE|', 'Bao|Weike|W|', 'Olzinski|Alan R|AR|', 'Guo|Yuanjun|Y|', 'Lal|Hind|H|', 'Eisennagel|Stephen H|SH|', 'Platchek|Michael C|MC|', 'Xie|Wensheng|W|', 'Del Rosario|Julius|J|', 'Nayal|Mohamad|M|', 'Lu|Quinn|Q|', 'Roethke|Theresa|T|', 'Schnackenberg|Christine G|CG|', 'Wright|Fe|F|', 'Quaile|Michael P|MP|', 'Halsey|Wendy S|WS|', 'Hughes|Ashley M|AM|', 'Sathe|Ganesh M|GM|', 'Livi|George P|GP|', 'Kirkpatrick|Robert B|RB|', 'Qu|Xiaoyan A|XA|', 'Rajpal|Deepak K|DK|', 'Faelth Savitski|Maria|M|', 'Bantscheff|Marcus|M|', 'Joberty|Gerard|G|', 'Bergamini|Giovanna|G|', 'Force|Thomas L|TL|', 'Gatto|Gregory J|GJ|', 'Hu|Erding|E|', 'Willette|Robert N|RN|']
D000596:Amino Acids D000604:Amino Acyl-tRNA Synthetases D000818:Animals D001343:Autophagy D002478:Cells, Cultured D004195:Disease Models, Animal D004305:Dose-Response Relationship, Drug D004791:Enzyme Inhibitors D005347:Fibroblasts D005355:Fibrosis D006333:Heart Failure D006801:Humans D017379:Hypertrophy, Left Ventricular D057026:Induced Pluripotent Stem Cells D008297:Male D008810:Mice, Inbred C57BL D032383:Myocytes, Cardiac D010880:Piperidines D017346:Protein Serine-Threonine Kinases D011500:Protein Synthesis Inhibitors D052999:Quinazolinones D013312:Stress, Physiological D013997:Time Factors D016277:Ventricular Function, Left D020257:Ventricular Remodeling
amino acid response halofuginone fibrosis hypertrophy heart failure