Catecholamine-Dependent β-Adrenergic Signaling in a Pluripotent Stem Cell Model of Takotsubo Cardiomyopathy
Takotsubo syndrome (TTS) is characterized by an acute left ventricular dysfunction and is associated with life-threating complications in the acute phase. The underlying disease mechanism in TTS is still unknown. A genetic basis has been suggested to be involved in the pathogenesis. The aims of the...
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| Veröffentlicht in: | Journal of the American College of Cardiology 2017-08, Vol.70 (8), p.975-991 |
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| creator | Borchert, Thomas Hübscher, Daniela Guessoum, Celina I. Lam, Tuan-Dinh D. Ghadri, Jelena R. Schellinger, Isabel N. Tiburcy, Malte Liaw, Norman Y. Li, Yun Haas, Jan Sossalla, Samuel Huber, Mia A. Cyganek, Lukas Jacobshagen, Claudius Dressel, Ralf Raaz, Uwe Nikolaev, Viacheslav O. Guan, Kaomei Thiele, Holger Meder, Benjamin Wollnik, Bernd Zimmermann, Wolfram-Hubertus Lüscher, Thomas F. Hasenfuss, Gerd Templin, Christian Streckfuss-Bömeke, Katrin |
| description | Takotsubo syndrome (TTS) is characterized by an acute left ventricular dysfunction and is associated with life-threating complications in the acute phase. The underlying disease mechanism in TTS is still unknown. A genetic basis has been suggested to be involved in the pathogenesis.
The aims of the study were to establish an in vitro induced pluripotent stem cell (iPSC) model of TTS, to test the hypothesis of altered β-adrenergic signaling in TTS iPSC-cardiomyocytes (CMs), and to explore whether genetic susceptibility underlies the pathophysiology of TTS.
Somatic cells of patients with TTS and control subjects were reprogrammed to iPSCs and differentiated into CMs. Three-month-old CMs were subjected to catecholamine stimulation to simulate neurohumoral overstimulation. We investigated β-adrenergic signaling and TTS cardiomyocyte function.
Enhanced β-adrenergic signaling in TTS-iPSC-CMs under catecholamine-induced stress increased expression of the cardiac stress marker NR4A1; cyclic adenosine monophosphate levels; and cyclic adenosine monophosphate–dependent protein kinase A–mediated hyperphosphorylation of RYR2-S2808, PLN-S16, TNI-S23/24, and Cav1.2-S1928, and leads to a reduced calcium time to transient 50% decay. These cellular catecholamine-dependent responses were mainly mediated by β1-adrenoceptor signaling in TTS. Engineered heart muscles from TTS-iPSC-CMs showed an impaired force of contraction and a higher sensitivity to isoprenaline-stimulated inotropy compared with control subjects. In addition, altered electrical activity and increased lipid accumulation were detected in catecholamine-treated TTS-iPSC-CMs, and were confirmed by differentially expressed lipid transporters CD36 and CPT1C. Furthermore, we uncovered genetic variants in different key regulators of cardiac function.
Enhanced β-adrenergic signaling and higher sensitivity to catecholamine-induced toxicity were identified as mechanisms associated with the TTS phenotype. (International Takotsubo Registry [InterTAK Registry] [InterTAK]; NCT01947621)
[Display omitted] |
| doi_str_mv | 10.1016/j.jacc.2017.06.061 |
| format | Article |
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The aims of the study were to establish an in vitro induced pluripotent stem cell (iPSC) model of TTS, to test the hypothesis of altered β-adrenergic signaling in TTS iPSC-cardiomyocytes (CMs), and to explore whether genetic susceptibility underlies the pathophysiology of TTS.
Somatic cells of patients with TTS and control subjects were reprogrammed to iPSCs and differentiated into CMs. Three-month-old CMs were subjected to catecholamine stimulation to simulate neurohumoral overstimulation. We investigated β-adrenergic signaling and TTS cardiomyocyte function.
Enhanced β-adrenergic signaling in TTS-iPSC-CMs under catecholamine-induced stress increased expression of the cardiac stress marker NR4A1; cyclic adenosine monophosphate levels; and cyclic adenosine monophosphate–dependent protein kinase A–mediated hyperphosphorylation of RYR2-S2808, PLN-S16, TNI-S23/24, and Cav1.2-S1928, and leads to a reduced calcium time to transient 50% decay. These cellular catecholamine-dependent responses were mainly mediated by β1-adrenoceptor signaling in TTS. Engineered heart muscles from TTS-iPSC-CMs showed an impaired force of contraction and a higher sensitivity to isoprenaline-stimulated inotropy compared with control subjects. In addition, altered electrical activity and increased lipid accumulation were detected in catecholamine-treated TTS-iPSC-CMs, and were confirmed by differentially expressed lipid transporters CD36 and CPT1C. Furthermore, we uncovered genetic variants in different key regulators of cardiac function.
Enhanced β-adrenergic signaling and higher sensitivity to catecholamine-induced toxicity were identified as mechanisms associated with the TTS phenotype. (International Takotsubo Registry [InterTAK Registry] [InterTAK]; NCT01947621)
[Display omitted]</description><identifier>ISSN: 0735-1097</identifier><identifier>EISSN: 1558-3597</identifier><identifier>DOI: 10.1016/j.jacc.2017.06.061</identifier><identifier>PMID: 28818208</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adenosine kinase ; Adenosine monophosphate ; Adrenergic receptors ; Adult ; broken heart syndrome ; Calcium ; Calcium channels (voltage-gated) ; Cardiac arrhythmia ; Cardiac muscle ; Cardiology ; Cardiomyocytes ; Cardiomyopathy ; Catecholamine ; Catecholamines ; Catecholamines - pharmacology ; Cell Differentiation ; Cells, Cultured ; Complications ; Computer simulation ; Contraction ; Cyclic AMP ; DNA methylation ; electrical activity ; Female ; Fibroblasts ; Heart ; Heart attacks ; Heart diseases ; Humans ; In vitro methods and tests ; Induced Pluripotent Stem Cells - metabolism ; Induced Pluripotent Stem Cells - pathology ; Inhibitory postsynaptic potentials ; iPSC cardiomyocytes ; Kinases ; Lipids ; lipotoxicity ; Metabolism ; Middle Aged ; Muscle contraction ; Muscles ; Myocytes, Cardiac - metabolism ; Myocytes, Cardiac - pathology ; Pathogenesis ; Patients ; Phase (cyclic) ; Phosphorylation ; Pluripotency ; Protein kinase A ; Receptors, Adrenergic, beta - metabolism ; Regulators ; Rodents ; Ryanodine receptors ; Sensitivity ; Signal Transduction ; Somatic cells ; Stem cells ; Stimulation ; Studies ; Takotsubo Cardiomyopathy - metabolism ; Takotsubo Cardiomyopathy - pathology ; Toxicity ; TTS pathogenesis ; Ventricle</subject><ispartof>Journal of the American College of Cardiology, 2017-08, Vol.70 (8), p.975-991</ispartof><rights>2017 The Authors</rights><rights>Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.</rights><rights>Copyright Elsevier Limited Aug 22, 2017</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c428t-43a4d159e7b6ae33b2d11371575469b3a8955487a5616e8f250efb597b094d603</citedby><cites>FETCH-LOGICAL-c428t-43a4d159e7b6ae33b2d11371575469b3a8955487a5616e8f250efb597b094d603</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0735109717380099$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28818208$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Borchert, Thomas</creatorcontrib><creatorcontrib>Hübscher, Daniela</creatorcontrib><creatorcontrib>Guessoum, Celina I.</creatorcontrib><creatorcontrib>Lam, Tuan-Dinh D.</creatorcontrib><creatorcontrib>Ghadri, Jelena R.</creatorcontrib><creatorcontrib>Schellinger, Isabel N.</creatorcontrib><creatorcontrib>Tiburcy, Malte</creatorcontrib><creatorcontrib>Liaw, Norman Y.</creatorcontrib><creatorcontrib>Li, Yun</creatorcontrib><creatorcontrib>Haas, Jan</creatorcontrib><creatorcontrib>Sossalla, Samuel</creatorcontrib><creatorcontrib>Huber, Mia A.</creatorcontrib><creatorcontrib>Cyganek, Lukas</creatorcontrib><creatorcontrib>Jacobshagen, Claudius</creatorcontrib><creatorcontrib>Dressel, Ralf</creatorcontrib><creatorcontrib>Raaz, Uwe</creatorcontrib><creatorcontrib>Nikolaev, Viacheslav O.</creatorcontrib><creatorcontrib>Guan, Kaomei</creatorcontrib><creatorcontrib>Thiele, Holger</creatorcontrib><creatorcontrib>Meder, Benjamin</creatorcontrib><creatorcontrib>Wollnik, Bernd</creatorcontrib><creatorcontrib>Zimmermann, Wolfram-Hubertus</creatorcontrib><creatorcontrib>Lüscher, Thomas F.</creatorcontrib><creatorcontrib>Hasenfuss, Gerd</creatorcontrib><creatorcontrib>Templin, Christian</creatorcontrib><creatorcontrib>Streckfuss-Bömeke, Katrin</creatorcontrib><title>Catecholamine-Dependent β-Adrenergic Signaling in a Pluripotent Stem Cell Model of Takotsubo Cardiomyopathy</title><title>Journal of the American College of Cardiology</title><addtitle>J Am Coll Cardiol</addtitle><description>Takotsubo syndrome (TTS) is characterized by an acute left ventricular dysfunction and is associated with life-threating complications in the acute phase. The underlying disease mechanism in TTS is still unknown. A genetic basis has been suggested to be involved in the pathogenesis.
The aims of the study were to establish an in vitro induced pluripotent stem cell (iPSC) model of TTS, to test the hypothesis of altered β-adrenergic signaling in TTS iPSC-cardiomyocytes (CMs), and to explore whether genetic susceptibility underlies the pathophysiology of TTS.
Somatic cells of patients with TTS and control subjects were reprogrammed to iPSCs and differentiated into CMs. Three-month-old CMs were subjected to catecholamine stimulation to simulate neurohumoral overstimulation. We investigated β-adrenergic signaling and TTS cardiomyocyte function.
Enhanced β-adrenergic signaling in TTS-iPSC-CMs under catecholamine-induced stress increased expression of the cardiac stress marker NR4A1; cyclic adenosine monophosphate levels; and cyclic adenosine monophosphate–dependent protein kinase A–mediated hyperphosphorylation of RYR2-S2808, PLN-S16, TNI-S23/24, and Cav1.2-S1928, and leads to a reduced calcium time to transient 50% decay. These cellular catecholamine-dependent responses were mainly mediated by β1-adrenoceptor signaling in TTS. Engineered heart muscles from TTS-iPSC-CMs showed an impaired force of contraction and a higher sensitivity to isoprenaline-stimulated inotropy compared with control subjects. In addition, altered electrical activity and increased lipid accumulation were detected in catecholamine-treated TTS-iPSC-CMs, and were confirmed by differentially expressed lipid transporters CD36 and CPT1C. Furthermore, we uncovered genetic variants in different key regulators of cardiac function.
Enhanced β-adrenergic signaling and higher sensitivity to catecholamine-induced toxicity were identified as mechanisms associated with the TTS phenotype. (International Takotsubo Registry [InterTAK Registry] [InterTAK]; NCT01947621)
[Display omitted]</description><subject>Adenosine kinase</subject><subject>Adenosine monophosphate</subject><subject>Adrenergic receptors</subject><subject>Adult</subject><subject>broken heart syndrome</subject><subject>Calcium</subject><subject>Calcium channels (voltage-gated)</subject><subject>Cardiac arrhythmia</subject><subject>Cardiac muscle</subject><subject>Cardiology</subject><subject>Cardiomyocytes</subject><subject>Cardiomyopathy</subject><subject>Catecholamine</subject><subject>Catecholamines</subject><subject>Catecholamines - pharmacology</subject><subject>Cell Differentiation</subject><subject>Cells, Cultured</subject><subject>Complications</subject><subject>Computer simulation</subject><subject>Contraction</subject><subject>Cyclic AMP</subject><subject>DNA methylation</subject><subject>electrical activity</subject><subject>Female</subject><subject>Fibroblasts</subject><subject>Heart</subject><subject>Heart attacks</subject><subject>Heart diseases</subject><subject>Humans</subject><subject>In vitro methods and tests</subject><subject>Induced Pluripotent Stem Cells - metabolism</subject><subject>Induced Pluripotent Stem Cells - pathology</subject><subject>Inhibitory postsynaptic potentials</subject><subject>iPSC cardiomyocytes</subject><subject>Kinases</subject><subject>Lipids</subject><subject>lipotoxicity</subject><subject>Metabolism</subject><subject>Middle Aged</subject><subject>Muscle contraction</subject><subject>Muscles</subject><subject>Myocytes, Cardiac - metabolism</subject><subject>Myocytes, Cardiac - pathology</subject><subject>Pathogenesis</subject><subject>Patients</subject><subject>Phase (cyclic)</subject><subject>Phosphorylation</subject><subject>Pluripotency</subject><subject>Protein kinase A</subject><subject>Receptors, Adrenergic, beta - metabolism</subject><subject>Regulators</subject><subject>Rodents</subject><subject>Ryanodine receptors</subject><subject>Sensitivity</subject><subject>Signal Transduction</subject><subject>Somatic cells</subject><subject>Stem cells</subject><subject>Stimulation</subject><subject>Studies</subject><subject>Takotsubo Cardiomyopathy - metabolism</subject><subject>Takotsubo Cardiomyopathy - pathology</subject><subject>Toxicity</subject><subject>TTS pathogenesis</subject><subject>Ventricle</subject><issn>0735-1097</issn><issn>1558-3597</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kN1q1UAUhQdR7Gn1BbyQgNc5zk4yf-BNSbUKLRVar4fJzM7pxCQTJxPhvI3P4CP4AD5Tczi1l8KGffOtBesj5A3QLVDg77ttZ6zdFhTElvL14BnZAGMyL5kSz8mGipLlQJU4Iafz3FFKuQT1kpwUUoIsqNyQoTYJ7X3ozeBHzC9wwtHhmLK_v_NzF3HEuPM2u_W70fR-3GV-zEz2tV-in0I6gLcJh6zGvs-ug8P-z6_QZnfme0jz0oSsNtH5MOzDZNL9_hV50Zp-xteP_4x8-_Txrv6cX91cfqnPr3JbFTLlVWkqB0yhaLjBsmwKB1AKYIJVXDWlkYqxSgrDOHCUbcEots26uaGqcpyWZ-TdsXeK4ceCc9JdWOK6YNagCiUkMJArVRwpG8M8R2z1FP1g4l4D1QfDutMHw_pgWFO-Hqyht4_VSzOge4r8U7oCH44ArgN_eox6th5Hi85HtEm74P_X_wCJHY2s</recordid><startdate>20170822</startdate><enddate>20170822</enddate><creator>Borchert, Thomas</creator><creator>Hübscher, Daniela</creator><creator>Guessoum, Celina I.</creator><creator>Lam, Tuan-Dinh D.</creator><creator>Ghadri, Jelena R.</creator><creator>Schellinger, Isabel N.</creator><creator>Tiburcy, Malte</creator><creator>Liaw, Norman Y.</creator><creator>Li, Yun</creator><creator>Haas, Jan</creator><creator>Sossalla, Samuel</creator><creator>Huber, Mia A.</creator><creator>Cyganek, Lukas</creator><creator>Jacobshagen, Claudius</creator><creator>Dressel, Ralf</creator><creator>Raaz, Uwe</creator><creator>Nikolaev, Viacheslav O.</creator><creator>Guan, Kaomei</creator><creator>Thiele, Holger</creator><creator>Meder, Benjamin</creator><creator>Wollnik, Bernd</creator><creator>Zimmermann, Wolfram-Hubertus</creator><creator>Lüscher, Thomas F.</creator><creator>Hasenfuss, Gerd</creator><creator>Templin, Christian</creator><creator>Streckfuss-Bömeke, Katrin</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TK</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope></search><sort><creationdate>20170822</creationdate><title>Catecholamine-Dependent β-Adrenergic Signaling in a Pluripotent Stem Cell Model of Takotsubo Cardiomyopathy</title><author>Borchert, Thomas ; Hübscher, Daniela ; Guessoum, Celina I. ; Lam, Tuan-Dinh D. ; Ghadri, Jelena R. ; Schellinger, Isabel N. ; Tiburcy, Malte ; Liaw, Norman Y. ; Li, Yun ; Haas, Jan ; Sossalla, Samuel ; Huber, Mia A. ; Cyganek, Lukas ; Jacobshagen, Claudius ; Dressel, Ralf ; Raaz, Uwe ; Nikolaev, Viacheslav O. ; Guan, Kaomei ; Thiele, Holger ; Meder, Benjamin ; Wollnik, Bernd ; Zimmermann, Wolfram-Hubertus ; Lüscher, Thomas F. ; Hasenfuss, Gerd ; Templin, Christian ; Streckfuss-Bömeke, Katrin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c428t-43a4d159e7b6ae33b2d11371575469b3a8955487a5616e8f250efb597b094d603</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Adenosine kinase</topic><topic>Adenosine monophosphate</topic><topic>Adrenergic receptors</topic><topic>Adult</topic><topic>broken heart syndrome</topic><topic>Calcium</topic><topic>Calcium channels (voltage-gated)</topic><topic>Cardiac arrhythmia</topic><topic>Cardiac muscle</topic><topic>Cardiology</topic><topic>Cardiomyocytes</topic><topic>Cardiomyopathy</topic><topic>Catecholamine</topic><topic>Catecholamines</topic><topic>Catecholamines - 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metabolism</topic><topic>Regulators</topic><topic>Rodents</topic><topic>Ryanodine receptors</topic><topic>Sensitivity</topic><topic>Signal Transduction</topic><topic>Somatic cells</topic><topic>Stem cells</topic><topic>Stimulation</topic><topic>Studies</topic><topic>Takotsubo Cardiomyopathy - metabolism</topic><topic>Takotsubo Cardiomyopathy - pathology</topic><topic>Toxicity</topic><topic>TTS pathogenesis</topic><topic>Ventricle</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Borchert, Thomas</creatorcontrib><creatorcontrib>Hübscher, Daniela</creatorcontrib><creatorcontrib>Guessoum, Celina I.</creatorcontrib><creatorcontrib>Lam, Tuan-Dinh D.</creatorcontrib><creatorcontrib>Ghadri, Jelena R.</creatorcontrib><creatorcontrib>Schellinger, Isabel N.</creatorcontrib><creatorcontrib>Tiburcy, Malte</creatorcontrib><creatorcontrib>Liaw, Norman Y.</creatorcontrib><creatorcontrib>Li, Yun</creatorcontrib><creatorcontrib>Haas, Jan</creatorcontrib><creatorcontrib>Sossalla, Samuel</creatorcontrib><creatorcontrib>Huber, Mia A.</creatorcontrib><creatorcontrib>Cyganek, Lukas</creatorcontrib><creatorcontrib>Jacobshagen, Claudius</creatorcontrib><creatorcontrib>Dressel, Ralf</creatorcontrib><creatorcontrib>Raaz, Uwe</creatorcontrib><creatorcontrib>Nikolaev, Viacheslav O.</creatorcontrib><creatorcontrib>Guan, Kaomei</creatorcontrib><creatorcontrib>Thiele, Holger</creatorcontrib><creatorcontrib>Meder, Benjamin</creatorcontrib><creatorcontrib>Wollnik, Bernd</creatorcontrib><creatorcontrib>Zimmermann, Wolfram-Hubertus</creatorcontrib><creatorcontrib>Lüscher, Thomas F.</creatorcontrib><creatorcontrib>Hasenfuss, Gerd</creatorcontrib><creatorcontrib>Templin, Christian</creatorcontrib><creatorcontrib>Streckfuss-Bömeke, Katrin</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><jtitle>Journal of the American College of Cardiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Borchert, Thomas</au><au>Hübscher, Daniela</au><au>Guessoum, Celina I.</au><au>Lam, Tuan-Dinh D.</au><au>Ghadri, Jelena R.</au><au>Schellinger, Isabel N.</au><au>Tiburcy, Malte</au><au>Liaw, Norman Y.</au><au>Li, Yun</au><au>Haas, Jan</au><au>Sossalla, Samuel</au><au>Huber, Mia A.</au><au>Cyganek, Lukas</au><au>Jacobshagen, Claudius</au><au>Dressel, Ralf</au><au>Raaz, Uwe</au><au>Nikolaev, Viacheslav O.</au><au>Guan, Kaomei</au><au>Thiele, Holger</au><au>Meder, Benjamin</au><au>Wollnik, Bernd</au><au>Zimmermann, Wolfram-Hubertus</au><au>Lüscher, Thomas F.</au><au>Hasenfuss, Gerd</au><au>Templin, Christian</au><au>Streckfuss-Bömeke, Katrin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Catecholamine-Dependent β-Adrenergic Signaling in a Pluripotent Stem Cell Model of Takotsubo Cardiomyopathy</atitle><jtitle>Journal of the American College of Cardiology</jtitle><addtitle>J Am Coll Cardiol</addtitle><date>2017-08-22</date><risdate>2017</risdate><volume>70</volume><issue>8</issue><spage>975</spage><epage>991</epage><pages>975-991</pages><issn>0735-1097</issn><eissn>1558-3597</eissn><abstract>Takotsubo syndrome (TTS) is characterized by an acute left ventricular dysfunction and is associated with life-threating complications in the acute phase. The underlying disease mechanism in TTS is still unknown. A genetic basis has been suggested to be involved in the pathogenesis.
The aims of the study were to establish an in vitro induced pluripotent stem cell (iPSC) model of TTS, to test the hypothesis of altered β-adrenergic signaling in TTS iPSC-cardiomyocytes (CMs), and to explore whether genetic susceptibility underlies the pathophysiology of TTS.
Somatic cells of patients with TTS and control subjects were reprogrammed to iPSCs and differentiated into CMs. Three-month-old CMs were subjected to catecholamine stimulation to simulate neurohumoral overstimulation. We investigated β-adrenergic signaling and TTS cardiomyocyte function.
Enhanced β-adrenergic signaling in TTS-iPSC-CMs under catecholamine-induced stress increased expression of the cardiac stress marker NR4A1; cyclic adenosine monophosphate levels; and cyclic adenosine monophosphate–dependent protein kinase A–mediated hyperphosphorylation of RYR2-S2808, PLN-S16, TNI-S23/24, and Cav1.2-S1928, and leads to a reduced calcium time to transient 50% decay. These cellular catecholamine-dependent responses were mainly mediated by β1-adrenoceptor signaling in TTS. Engineered heart muscles from TTS-iPSC-CMs showed an impaired force of contraction and a higher sensitivity to isoprenaline-stimulated inotropy compared with control subjects. In addition, altered electrical activity and increased lipid accumulation were detected in catecholamine-treated TTS-iPSC-CMs, and were confirmed by differentially expressed lipid transporters CD36 and CPT1C. Furthermore, we uncovered genetic variants in different key regulators of cardiac function.
Enhanced β-adrenergic signaling and higher sensitivity to catecholamine-induced toxicity were identified as mechanisms associated with the TTS phenotype. (International Takotsubo Registry [InterTAK Registry] [InterTAK]; NCT01947621)
[Display omitted]</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>28818208</pmid><doi>10.1016/j.jacc.2017.06.061</doi><tpages>17</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0735-1097 |
| ispartof | Journal of the American College of Cardiology, 2017-08, Vol.70 (8), p.975-991 |
| issn | 0735-1097 1558-3597 |
| language | eng |
| recordid | cdi_proquest_journals_1929781518 |
| source | MEDLINE; Elsevier ScienceDirect Journals Complete; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Adenosine kinase Adenosine monophosphate Adrenergic receptors Adult broken heart syndrome Calcium Calcium channels (voltage-gated) Cardiac arrhythmia Cardiac muscle Cardiology Cardiomyocytes Cardiomyopathy Catecholamine Catecholamines Catecholamines - pharmacology Cell Differentiation Cells, Cultured Complications Computer simulation Contraction Cyclic AMP DNA methylation electrical activity Female Fibroblasts Heart Heart attacks Heart diseases Humans In vitro methods and tests Induced Pluripotent Stem Cells - metabolism Induced Pluripotent Stem Cells - pathology Inhibitory postsynaptic potentials iPSC cardiomyocytes Kinases Lipids lipotoxicity Metabolism Middle Aged Muscle contraction Muscles Myocytes, Cardiac - metabolism Myocytes, Cardiac - pathology Pathogenesis Patients Phase (cyclic) Phosphorylation Pluripotency Protein kinase A Receptors, Adrenergic, beta - metabolism Regulators Rodents Ryanodine receptors Sensitivity Signal Transduction Somatic cells Stem cells Stimulation Studies Takotsubo Cardiomyopathy - metabolism Takotsubo Cardiomyopathy - pathology Toxicity TTS pathogenesis Ventricle |
| title | Catecholamine-Dependent β-Adrenergic Signaling in a Pluripotent Stem Cell Model of Takotsubo Cardiomyopathy |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-11T14%3A31%3A57IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_cross&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Catecholamine-Dependent%20%CE%B2-Adrenergic%20Signaling%20in%20a%20Pluripotent%20Stem%20Cell%20Model%C2%A0of%20Takotsubo%20Cardiomyopathy&rft.jtitle=Journal%20of%20the%20American%20College%20of%20Cardiology&rft.au=Borchert,%20Thomas&rft.date=2017-08-22&rft.volume=70&rft.issue=8&rft.spage=975&rft.epage=991&rft.pages=975-991&rft.issn=0735-1097&rft.eissn=1558-3597&rft_id=info:doi/10.1016/j.jacc.2017.06.061&rft_dat=%3Cproquest_cross%3E1929781518%3C/proquest_cross%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1929781518&rft_id=info:pmid/28818208&rft_els_id=S0735109717380099&rfr_iscdi=true |