Activation of the Amino Acid Response Pathway Blunts the Effects of Cardiac Stress
BackgroundThe 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...
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| Format: | Article |
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Wiley
2017-05-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
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| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.116.004453 |
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| author | Pu Qin Pelin Arabacilar Roberta E. Bernard Weike Bao Alan R. Olzinski Yuanjun Guo Hind Lal Stephen H. Eisennagel Michael C. Platchek Wensheng Xie Julius del Rosario Mohamad Nayal Quinn Lu Theresa Roethke Christine G. Schnackenberg Fe Wright Michael P. Quaile Wendy S. Halsey Ashley M. Hughes Ganesh M. Sathe George P. Livi Robert B. Kirkpatrick Xiaoyan A. Qu Deepak K. Rajpal Maria Faelth Savitski Marcus Bantscheff Gerard Joberty Giovanna Bergamini Thomas L. Force Gregory J. Gatto Erding Hu Robert N. Willette |
| author_facet | Pu Qin Pelin Arabacilar Roberta E. Bernard Weike Bao Alan R. Olzinski Yuanjun Guo Hind Lal Stephen H. Eisennagel Michael C. Platchek Wensheng Xie Julius del Rosario Mohamad Nayal Quinn Lu Theresa Roethke Christine G. Schnackenberg Fe Wright Michael P. Quaile Wendy S. Halsey Ashley M. Hughes Ganesh M. Sathe George P. Livi Robert B. Kirkpatrick Xiaoyan A. Qu Deepak K. Rajpal Maria Faelth Savitski Marcus Bantscheff Gerard Joberty Giovanna Bergamini Thomas L. Force Gregory J. Gatto Erding Hu Robert N. Willette |
| author_sort | Pu Qin |
| collection | DOAJ |
| description | BackgroundThe 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 ResultsConsistent 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. ConclusionsHalofuginone activated the AAR pathway in the heart and attenuated the structural and functional effects of cardiac stress. |
| first_indexed | 2024-04-13T15:36:16Z |
| format | Article |
| id | doaj.art-1c805dc589c7489c9f517443145877c9 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-04-13T15:36:16Z |
| publishDate | 2017-05-01 |
| publisher | Wiley |
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| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-1c805dc589c7489c9f517443145877c92022-12-22T02:41:16ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802017-05-016510.1161/JAHA.116.004453Activation of the Amino Acid Response Pathway Blunts the Effects of Cardiac StressPu Qin0Pelin Arabacilar1Roberta E. Bernard2Weike Bao3Alan R. Olzinski4Yuanjun Guo5Hind Lal6Stephen H. Eisennagel7Michael C. Platchek8Wensheng Xie9Julius del Rosario10Mohamad Nayal11Quinn Lu12Theresa Roethke13Christine G. Schnackenberg14Fe Wright15Michael P. Quaile16Wendy S. Halsey17Ashley M. Hughes18Ganesh M. Sathe19George P. Livi20Robert B. Kirkpatrick21Xiaoyan A. Qu22Deepak K. Rajpal23Maria Faelth Savitski24Marcus Bantscheff25Gerard Joberty26Giovanna Bergamini27Thomas L. Force28Gregory J. Gatto29Erding Hu30Robert N. Willette31Heart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapy Area GlaxoSmithKline, King of Prussia, PAHeart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapy Area GlaxoSmithKline, King of Prussia, PAHeart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapy Area GlaxoSmithKline, King of Prussia, PAHeart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapy Area GlaxoSmithKline, King of Prussia, PAHeart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapy Area GlaxoSmithKline, King of Prussia, PABasic & Translational Research, School of Medicine, Vanderbilt University, Nashville, TNBasic & Translational Research, School of Medicine, Vanderbilt University, Nashville, TNHeart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapy Area GlaxoSmithKline, King of Prussia, PATarget and Pathway Validation, Target Sciences, GlaxoSmithKline, King of Prussia, PATarget and Pathway Validation, Target Sciences, GlaxoSmithKline, King of Prussia, PAHeart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapy Area GlaxoSmithKline, King of Prussia, PAHeart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapy Area GlaxoSmithKline, King of Prussia, PATarget and Pathway Validation, Target Sciences, GlaxoSmithKline, King of Prussia, PAHeart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapy Area GlaxoSmithKline, King of Prussia, PAHeart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapy Area GlaxoSmithKline, King of Prussia, PAPreclinical and Translational Imaging, Platform Technology and Science, GlaxoSmithKline, King of Prussia, PAPreclinical and Translational Imaging, Platform Technology and Science, GlaxoSmithKline, King of Prussia, PATarget and Pathway Validation, Target Sciences, GlaxoSmithKline, King of Prussia, PATarget and Pathway Validation, Target Sciences, GlaxoSmithKline, King of Prussia, PATarget and Pathway Validation, Target Sciences, GlaxoSmithKline, King of Prussia, PATarget and Pathway Validation, Target Sciences, GlaxoSmithKline, King of Prussia, PAPipeline Future's Group, GlaxoSmithKline, King of Prussia, PAComputational Biology, Projects Clinical Platforms and Sciences, GlaxoSmithKline, King of Prussia, PAComputational Biology, Projects Clinical Platforms and Sciences, GlaxoSmithKline, King of Prussia, PACellzome GmbH, A GSK Company, GlaxoSmithKline, King of Prussia, PACellzome GmbH, A GSK Company, GlaxoSmithKline, King of Prussia, PACellzome GmbH, A GSK Company, GlaxoSmithKline, King of Prussia, PACellzome GmbH, A GSK Company, GlaxoSmithKline, King of Prussia, PABasic & Translational Research, School of Medicine, Vanderbilt University, Nashville, TNHeart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapy Area GlaxoSmithKline, King of Prussia, PAHeart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapy Area GlaxoSmithKline, King of Prussia, PAHeart Failure Discovery Performance Unit, Metabolic Pathways and Cardiovascular Therapy Area GlaxoSmithKline, King of Prussia, PABackgroundThe 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 ResultsConsistent 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. ConclusionsHalofuginone activated the AAR pathway in the heart and attenuated the structural and functional effects of cardiac stress.https://www.ahajournals.org/doi/10.1161/JAHA.116.004453amino acid responsefibrosishalofuginoneheart failurehypertrophy |
| spellingShingle | Pu Qin Pelin Arabacilar Roberta E. Bernard Weike Bao Alan R. Olzinski Yuanjun Guo Hind Lal Stephen H. Eisennagel Michael C. Platchek Wensheng Xie Julius del Rosario Mohamad Nayal Quinn Lu Theresa Roethke Christine G. Schnackenberg Fe Wright Michael P. Quaile Wendy S. Halsey Ashley M. Hughes Ganesh M. Sathe George P. Livi Robert B. Kirkpatrick Xiaoyan A. Qu Deepak K. Rajpal Maria Faelth Savitski Marcus Bantscheff Gerard Joberty Giovanna Bergamini Thomas L. Force Gregory J. Gatto Erding Hu Robert N. Willette Activation of the Amino Acid Response Pathway Blunts the Effects of Cardiac Stress Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease amino acid response fibrosis halofuginone heart failure hypertrophy |
| title | Activation of the Amino Acid Response Pathway Blunts the Effects of Cardiac Stress |
| title_full | Activation of the Amino Acid Response Pathway Blunts the Effects of Cardiac Stress |
| title_fullStr | Activation of the Amino Acid Response Pathway Blunts the Effects of Cardiac Stress |
| title_full_unstemmed | Activation of the Amino Acid Response Pathway Blunts the Effects of Cardiac Stress |
| title_short | Activation of the Amino Acid Response Pathway Blunts the Effects of Cardiac Stress |
| title_sort | activation of the amino acid response pathway blunts the effects of cardiac stress |
| topic | amino acid response fibrosis halofuginone heart failure hypertrophy |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.116.004453 |
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