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Activation of the Amino Acid Response Pathway Blunts the Effects of Cardiac Stress
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| Zeitschriftentitel: | Journal of the American Heart Association |
|---|---|
| Personen und Körperschaften: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
| In: | Journal of the American Heart Association, 6, 2017, 5 |
| Format: | E-Article |
| Sprache: | Englisch |
| veröffentlicht: |
Ovid Technologies (Wolters Kluwer Health)
|
| Schlagwörter: |
| author_facet |
Qin, Pu Arabacilar, Pelin Bernard, Roberta E. Bao, Weike Olzinski, Alan R. Guo, Yuanjun Lal, Hind Eisennagel, Stephen H. Platchek, Michael C. Xie, Wensheng del Rosario, Julius Nayal, Mohamad Lu, Quinn Roethke, Theresa Schnackenberg, Christine G. Wright, Fe Quaile, Michael P. Halsey, Wendy S. Hughes, Ashley M. Sathe, Ganesh M. Livi, George P. Kirkpatrick, Robert B. Qu, Xiaoyan A. Rajpal, Deepak K. Faelth Savitski, Maria Bantscheff, Marcus Joberty, Gerard Bergamini, Giovanna Force, Thomas L. Gatto, Gregory J. Hu, Erding Willette, Robert N. Qin, Pu Arabacilar, Pelin Bernard, Roberta E. Bao, Weike Olzinski, Alan R. Guo, Yuanjun Lal, Hind Eisennagel, Stephen H. Platchek, Michael C. Xie, Wensheng del Rosario, Julius Nayal, Mohamad Lu, Quinn Roethke, Theresa Schnackenberg, Christine G. Wright, Fe Quaile, Michael P. Halsey, Wendy S. Hughes, Ashley M. Sathe, Ganesh M. Livi, George P. Kirkpatrick, Robert B. Qu, Xiaoyan A. Rajpal, Deepak K. Faelth Savitski, Maria Bantscheff, Marcus Joberty, Gerard Bergamini, Giovanna Force, Thomas L. Gatto, Gregory J. Hu, Erding Willette, Robert N. |
|---|---|
| author |
Qin, Pu Arabacilar, Pelin Bernard, Roberta E. Bao, Weike Olzinski, Alan R. Guo, Yuanjun Lal, Hind Eisennagel, Stephen H. Platchek, Michael C. Xie, Wensheng del Rosario, Julius Nayal, Mohamad Lu, Quinn Roethke, Theresa Schnackenberg, Christine G. Wright, Fe Quaile, Michael P. Halsey, Wendy S. Hughes, Ashley M. Sathe, Ganesh M. Livi, George P. Kirkpatrick, Robert B. Qu, Xiaoyan A. Rajpal, Deepak K. Faelth Savitski, Maria Bantscheff, Marcus Joberty, Gerard Bergamini, Giovanna Force, Thomas L. Gatto, Gregory J. Hu, Erding Willette, Robert N. |
| spellingShingle |
Qin, Pu Arabacilar, Pelin Bernard, Roberta E. Bao, Weike Olzinski, Alan R. Guo, Yuanjun Lal, Hind Eisennagel, Stephen H. Platchek, Michael C. Xie, Wensheng del Rosario, Julius Nayal, Mohamad Lu, Quinn Roethke, Theresa Schnackenberg, Christine G. Wright, Fe Quaile, Michael P. Halsey, Wendy S. Hughes, Ashley M. Sathe, Ganesh M. Livi, George P. Kirkpatrick, Robert B. Qu, Xiaoyan A. Rajpal, Deepak K. Faelth Savitski, Maria Bantscheff, Marcus Joberty, Gerard Bergamini, Giovanna Force, Thomas L. Gatto, Gregory J. Hu, Erding Willette, Robert N. Journal of the American Heart Association Activation of the Amino Acid Response Pathway Blunts the Effects of Cardiac Stress Cardiology and Cardiovascular Medicine |
| author_sort |
qin, pu |
| spelling |
Qin, Pu Arabacilar, Pelin Bernard, Roberta E. Bao, Weike Olzinski, Alan R. Guo, Yuanjun Lal, Hind Eisennagel, Stephen H. Platchek, Michael C. Xie, Wensheng del Rosario, Julius Nayal, Mohamad Lu, Quinn Roethke, Theresa Schnackenberg, Christine G. Wright, Fe Quaile, Michael P. Halsey, Wendy S. Hughes, Ashley M. Sathe, Ganesh M. Livi, George P. Kirkpatrick, Robert B. Qu, Xiaoyan A. Rajpal, Deepak K. Faelth Savitski, Maria Bantscheff, Marcus Joberty, Gerard Bergamini, Giovanna Force, Thomas L. Gatto, Gregory J. Hu, Erding Willette, Robert N. 2047-9980 Ovid Technologies (Wolters Kluwer Health) Cardiology and Cardiovascular Medicine http://dx.doi.org/10.1161/jaha.116.004453 <jats:sec xml:lang="en"> <jats:title>Background</jats:title> <jats:p xml:lang="en"> The amino acid response ( <jats:styled-content style="fixed-case">AAR</jats:styled-content> ) 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 <jats:styled-content style="fixed-case">AAR</jats:styled-content> 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‐ <jats:styled-content style="fixed-case">tRNA</jats:styled-content> synthetase inhibitor, on the <jats:styled-content style="fixed-case">AAR</jats:styled-content> pathway in cardiac fibroblasts, cardiomyocytes, and in mouse models of cardiac stress and failure. </jats:p> </jats:sec> <jats:sec xml:lang="en"> <jats:title>Methods and Results</jats:title> <jats:p xml:lang="en"> Consistent with its ability to inhibit prolyl‐ <jats:styled-content style="fixed-case">tRNA</jats:styled-content> synthetase, halofuginone elicited a general control nonderepressible 2–dependent activation of the <jats:styled-content style="fixed-case">AAR</jats:styled-content> pathway in cardiac fibroblasts as evidenced by activation of known <jats:styled-content style="fixed-case">AAR</jats:styled-content> target genes, broad regulation of the transcriptome and proteome, and reversal by <jats:sc>l</jats:sc> ‐proline supplementation. Halofuginone was examined in 3 mouse models of cardiac stress: angiotensin <jats:styled-content style="fixed-case">II</jats:styled-content> /phenylephrine, transverse aortic constriction, and acute ischemia reperfusion injury. It activated the <jats:styled-content style="fixed-case">AAR</jats:styled-content> 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/ <jats:styled-content style="fixed-case">eIF</jats:styled-content> 2α‐dependent manner. </jats:p> </jats:sec> <jats:sec xml:lang="en"> <jats:title>Conclusions</jats:title> <jats:p xml:lang="en"> Halofuginone activated the <jats:styled-content style="fixed-case">AAR</jats:styled-content> pathway in the heart and attenuated the structural and functional effects of cardiac stress. </jats:p> </jats:sec> Activation of the Amino Acid Response Pathway Blunts the Effects of Cardiac Stress Journal of the American Heart Association |
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2017 |
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Ovid Technologies (Wolters Kluwer Health) |
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Journal of the American Heart Association |
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| title |
Activation of the Amino Acid Response Pathway Blunts the Effects of Cardiac Stress |
| title_unstemmed |
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 |
Cardiology and Cardiovascular Medicine |
| url |
http://dx.doi.org/10.1161/jaha.116.004453 |
| publishDate |
2017 |
| physical |
|
| description |
<jats:sec xml:lang="en">
<jats:title>Background</jats:title>
<jats:p xml:lang="en">
The amino acid response (
<jats:styled-content style="fixed-case">AAR</jats:styled-content>
) 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
<jats:styled-content style="fixed-case">AAR</jats:styled-content>
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‐
<jats:styled-content style="fixed-case">tRNA</jats:styled-content>
synthetase inhibitor, on the
<jats:styled-content style="fixed-case">AAR</jats:styled-content>
pathway in cardiac fibroblasts, cardiomyocytes, and in mouse models of cardiac stress and failure.
</jats:p>
</jats:sec>
<jats:sec xml:lang="en">
<jats:title>Methods and Results</jats:title>
<jats:p xml:lang="en">
Consistent with its ability to inhibit prolyl‐
<jats:styled-content style="fixed-case">tRNA</jats:styled-content>
synthetase, halofuginone elicited a general control nonderepressible 2–dependent activation of the
<jats:styled-content style="fixed-case">AAR</jats:styled-content>
pathway in cardiac fibroblasts as evidenced by activation of known
<jats:styled-content style="fixed-case">AAR</jats:styled-content>
target genes, broad regulation of the transcriptome and proteome, and reversal by
<jats:sc>l</jats:sc>
‐proline supplementation. Halofuginone was examined in 3 mouse models of cardiac stress: angiotensin
<jats:styled-content style="fixed-case">II</jats:styled-content>
/phenylephrine, transverse aortic constriction, and acute ischemia reperfusion injury. It activated the
<jats:styled-content style="fixed-case">AAR</jats:styled-content>
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/
<jats:styled-content style="fixed-case">eIF</jats:styled-content>
2α‐dependent manner.
</jats:p>
</jats:sec>
<jats:sec xml:lang="en">
<jats:title>Conclusions</jats:title>
<jats:p xml:lang="en">
Halofuginone activated the
<jats:styled-content style="fixed-case">AAR</jats:styled-content>
pathway in the heart and attenuated the structural and functional effects of cardiac stress.
</jats:p>
</jats:sec> |
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| author | Qin, Pu, Arabacilar, Pelin, Bernard, Roberta E., Bao, Weike, Olzinski, Alan R., Guo, Yuanjun, Lal, Hind, Eisennagel, Stephen H., Platchek, Michael C., Xie, Wensheng, del Rosario, Julius, Nayal, Mohamad, Lu, Quinn, Roethke, Theresa, Schnackenberg, Christine G., Wright, Fe, Quaile, Michael P., Halsey, Wendy S., Hughes, Ashley M., Sathe, Ganesh M., Livi, George P., Kirkpatrick, Robert B., Qu, Xiaoyan A., Rajpal, Deepak K., Faelth Savitski, Maria, Bantscheff, Marcus, Joberty, Gerard, Bergamini, Giovanna, Force, Thomas L., Gatto, Gregory J., Hu, Erding, Willette, Robert N. |
| author_facet | Qin, Pu, Arabacilar, Pelin, Bernard, Roberta E., Bao, Weike, Olzinski, Alan R., Guo, Yuanjun, Lal, Hind, Eisennagel, Stephen H., Platchek, Michael C., Xie, Wensheng, del Rosario, Julius, Nayal, Mohamad, Lu, Quinn, Roethke, Theresa, Schnackenberg, Christine G., Wright, Fe, Quaile, Michael P., Halsey, Wendy S., Hughes, Ashley M., Sathe, Ganesh M., Livi, George P., Kirkpatrick, Robert B., Qu, Xiaoyan A., Rajpal, Deepak K., Faelth Savitski, Maria, Bantscheff, Marcus, Joberty, Gerard, Bergamini, Giovanna, Force, Thomas L., Gatto, Gregory J., Hu, Erding, Willette, Robert N., Qin, Pu, Arabacilar, Pelin, Bernard, Roberta E., Bao, Weike, Olzinski, Alan R., Guo, Yuanjun, Lal, Hind, Eisennagel, Stephen H., Platchek, Michael C., Xie, Wensheng, del Rosario, Julius, Nayal, Mohamad, Lu, Quinn, Roethke, Theresa, Schnackenberg, Christine G., Wright, Fe, Quaile, Michael P., Halsey, Wendy S., Hughes, Ashley M., Sathe, Ganesh M., Livi, George P., Kirkpatrick, Robert B., Qu, Xiaoyan A., Rajpal, Deepak K., Faelth Savitski, Maria, Bantscheff, Marcus, Joberty, Gerard, Bergamini, Giovanna, Force, Thomas L., Gatto, Gregory J., Hu, Erding, Willette, Robert N. |
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| description | <jats:sec xml:lang="en"> <jats:title>Background</jats:title> <jats:p xml:lang="en"> The amino acid response ( <jats:styled-content style="fixed-case">AAR</jats:styled-content> ) 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 <jats:styled-content style="fixed-case">AAR</jats:styled-content> 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‐ <jats:styled-content style="fixed-case">tRNA</jats:styled-content> synthetase inhibitor, on the <jats:styled-content style="fixed-case">AAR</jats:styled-content> pathway in cardiac fibroblasts, cardiomyocytes, and in mouse models of cardiac stress and failure. </jats:p> </jats:sec> <jats:sec xml:lang="en"> <jats:title>Methods and Results</jats:title> <jats:p xml:lang="en"> Consistent with its ability to inhibit prolyl‐ <jats:styled-content style="fixed-case">tRNA</jats:styled-content> synthetase, halofuginone elicited a general control nonderepressible 2–dependent activation of the <jats:styled-content style="fixed-case">AAR</jats:styled-content> pathway in cardiac fibroblasts as evidenced by activation of known <jats:styled-content style="fixed-case">AAR</jats:styled-content> target genes, broad regulation of the transcriptome and proteome, and reversal by <jats:sc>l</jats:sc> ‐proline supplementation. Halofuginone was examined in 3 mouse models of cardiac stress: angiotensin <jats:styled-content style="fixed-case">II</jats:styled-content> /phenylephrine, transverse aortic constriction, and acute ischemia reperfusion injury. It activated the <jats:styled-content style="fixed-case">AAR</jats:styled-content> 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/ <jats:styled-content style="fixed-case">eIF</jats:styled-content> 2α‐dependent manner. </jats:p> </jats:sec> <jats:sec xml:lang="en"> <jats:title>Conclusions</jats:title> <jats:p xml:lang="en"> Halofuginone activated the <jats:styled-content style="fixed-case">AAR</jats:styled-content> pathway in the heart and attenuated the structural and functional effects of cardiac stress. </jats:p> </jats:sec> |
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| spelling | Qin, Pu Arabacilar, Pelin Bernard, Roberta E. Bao, Weike Olzinski, Alan R. Guo, Yuanjun Lal, Hind Eisennagel, Stephen H. Platchek, Michael C. Xie, Wensheng del Rosario, Julius Nayal, Mohamad Lu, Quinn Roethke, Theresa Schnackenberg, Christine G. Wright, Fe Quaile, Michael P. Halsey, Wendy S. Hughes, Ashley M. Sathe, Ganesh M. Livi, George P. Kirkpatrick, Robert B. Qu, Xiaoyan A. Rajpal, Deepak K. Faelth Savitski, Maria Bantscheff, Marcus Joberty, Gerard Bergamini, Giovanna Force, Thomas L. Gatto, Gregory J. Hu, Erding Willette, Robert N. 2047-9980 Ovid Technologies (Wolters Kluwer Health) Cardiology and Cardiovascular Medicine http://dx.doi.org/10.1161/jaha.116.004453 <jats:sec xml:lang="en"> <jats:title>Background</jats:title> <jats:p xml:lang="en"> The amino acid response ( <jats:styled-content style="fixed-case">AAR</jats:styled-content> ) 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 <jats:styled-content style="fixed-case">AAR</jats:styled-content> 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‐ <jats:styled-content style="fixed-case">tRNA</jats:styled-content> synthetase inhibitor, on the <jats:styled-content style="fixed-case">AAR</jats:styled-content> pathway in cardiac fibroblasts, cardiomyocytes, and in mouse models of cardiac stress and failure. </jats:p> </jats:sec> <jats:sec xml:lang="en"> <jats:title>Methods and Results</jats:title> <jats:p xml:lang="en"> Consistent with its ability to inhibit prolyl‐ <jats:styled-content style="fixed-case">tRNA</jats:styled-content> synthetase, halofuginone elicited a general control nonderepressible 2–dependent activation of the <jats:styled-content style="fixed-case">AAR</jats:styled-content> pathway in cardiac fibroblasts as evidenced by activation of known <jats:styled-content style="fixed-case">AAR</jats:styled-content> target genes, broad regulation of the transcriptome and proteome, and reversal by <jats:sc>l</jats:sc> ‐proline supplementation. Halofuginone was examined in 3 mouse models of cardiac stress: angiotensin <jats:styled-content style="fixed-case">II</jats:styled-content> /phenylephrine, transverse aortic constriction, and acute ischemia reperfusion injury. It activated the <jats:styled-content style="fixed-case">AAR</jats:styled-content> 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/ <jats:styled-content style="fixed-case">eIF</jats:styled-content> 2α‐dependent manner. </jats:p> </jats:sec> <jats:sec xml:lang="en"> <jats:title>Conclusions</jats:title> <jats:p xml:lang="en"> Halofuginone activated the <jats:styled-content style="fixed-case">AAR</jats:styled-content> pathway in the heart and attenuated the structural and functional effects of cardiac stress. </jats:p> </jats:sec> Activation of the Amino Acid Response Pathway Blunts the Effects of Cardiac Stress Journal of the American Heart Association |
| spellingShingle | Qin, Pu, Arabacilar, Pelin, Bernard, Roberta E., Bao, Weike, Olzinski, Alan R., Guo, Yuanjun, Lal, Hind, Eisennagel, Stephen H., Platchek, Michael C., Xie, Wensheng, del Rosario, Julius, Nayal, Mohamad, Lu, Quinn, Roethke, Theresa, Schnackenberg, Christine G., Wright, Fe, Quaile, Michael P., Halsey, Wendy S., Hughes, Ashley M., Sathe, Ganesh M., Livi, George P., Kirkpatrick, Robert B., Qu, Xiaoyan A., Rajpal, Deepak K., Faelth Savitski, Maria, Bantscheff, Marcus, Joberty, Gerard, Bergamini, Giovanna, Force, Thomas L., Gatto, Gregory J., Hu, Erding, Willette, Robert N., Journal of the American Heart Association, Activation of the Amino Acid Response Pathway Blunts the Effects of Cardiac Stress, Cardiology and Cardiovascular Medicine |
| 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 |
| title_unstemmed | Activation of the Amino Acid Response Pathway Blunts the Effects of Cardiac Stress |
| topic | Cardiology and Cardiovascular Medicine |
| url | http://dx.doi.org/10.1161/jaha.116.004453 |