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. © 2017 the authors.