Active inhibitor-1 maintains protein hyper-phosphorylation in aging hearts and halts remodeling in failing hearts
Impaired sarcoplasmic reticulum calcium cycling and depressed contractility are key characteristics in heart failure. Defects in sarcoplasmic reticulum function are characterized by decreased SERCA2a Ca-transport that is partially attributable to dephosphorylation of its regulator phospholamban by i...
Gespeichert in:
| Veröffentlicht in: | PloS one 2013-12, Vol.8 (12), p.e80717-e80717 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Schlagworte: | |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | e80717 |
|---|---|
| container_issue | 12 |
| container_start_page | e80717 |
| container_title | PloS one |
| container_volume | 8 |
| creator | Pritchard, Tracy J Kawase, Yoshiaki Haghighi, Kobra Anjak, Ahmad Cai, Wenfeng Jiang, Min Nicolaou, Persoulla Pylar, George Karakikes, Ioannis Rapti, Kleopatra Rubinstein, Jack Hajjar, Roger J Kranias, Evangelia G |
| description | Impaired sarcoplasmic reticulum calcium cycling and depressed contractility are key characteristics in heart failure. Defects in sarcoplasmic reticulum function are characterized by decreased SERCA2a Ca-transport that is partially attributable to dephosphorylation of its regulator phospholamban by increased protein phosphatase 1 activity. Inhibition of protein phosphatase 1 through activation of its endogenous inhibitor-1 has been shown to enhance cardiac Ca-handling and contractility as well as protect from pathological stress remodeling in young mice. In this study, we assessed the long-term effects of inducible expression of constitutively active inhibitor-1 in the adult heart and followed function and remodeling through the aging process, up to 20 months. Mice with inhibitor-1 had normal survival and similar function to WTs. There was no overt remodeling as evidenced by measures of left ventricular end-systolic and diastolic diameters and posterior wall dimensions, heart weight to tibia length ratio, and histology. Higher phosphorylation of phospholamban at both Ser16 and Thr17 was maintained in aged hearts with active inhibitor-1, potentially offsetting the effects of elevated Ser2815-phosphorylation in ryanodine receptor, as there were no increases in arrhythmias under stress conditions in 20-month old mice. Furthermore, long-term expression of active inhibitor-1 via recombinant adeno-associated virus type 9 gene transfer in rats with pressure-overload induced heart failure improved function and prevented remodeling, associated with increased phosphorylation of phospholamban at Ser16 and Thr17. Thus, chronic inhibition of protein phosphatase 1, through increases in active inhibitor-1, does not accelerate age-related cardiomyopathy and gene transfer of this molecule in vivo improves function and halts remodeling in the long term. |
| doi_str_mv | 10.1371/journal.pone.0080717 |
| format | Article |
| fullrecord | <record><control><sourceid>gale_plos_</sourceid><recordid>TN_cdi_plos_journals_1463094859</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A478444439</galeid><doaj_id>oai_doaj_org_article_914668e255514939a6d21b2a33846d2f</doaj_id><sourcerecordid>A478444439</sourcerecordid><originalsourceid>FETCH-LOGICAL-c692t-941d79ff7133c513f75f855283b9fe172ea0d0e5a8126e3fc9d79534ed4329a93</originalsourceid><addsrcrecordid>eNqNk1uLnDAUx6W0dC_tNyitUCjtg1NzU_NSGJZeBhYWensNGU00Q0zcJC6db79xx92OZR-qBA_J7__PSTwnSV6BfAVQCT7u7OgM16vBGrHK8yovQfkkOQUUwayAOXp6FJ8kZ97v8pygqiieJycQIwAxLU6T63Ud1I1IlenUVgXrMpD2XJkQh08HZ4NQJu32g3DZ0Fkfh9trHpQ1UZPyVpk27QR3wafcNGnHdYyc6G0j9LQWIcmV_ou9SJ5Jrr14OX_Pk19fPv-8-JZdXn3dXKwvs7qgMGQUg6akUpYAoZoAJEsiK0JghbZUClBCwfMmF4RXABYCyZpGnCAsGowg5RSdJ28OvoO2ns235RnABcoprshEbA5EY_mODU713O2Z5YrdTVjXspiwqrVgNMqKSkBCCMAUUV40EGwhR6jCMZTR69O827jtRVMLExzXC9PlilEda-0NmwxICaPB-9nA2etR-MB65WuhNTfCjnd5k6ogAE55v_0Hffx0M9XyeABlpI371pMpW-OywvFBE7V6hIpvI3pVx9KSKs4vBB8WgsgE8Se0fPSebX58_3_26veSfXfExlLRofNWj1Ol-SWID2DtrPdOyIdLBjmbOuP-NtjUGWzujCh7ffyDHkT3rYBuAUaSCLw</addsrcrecordid><sourcetype>Open Website</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1463094859</pqid></control><display><type>article</type><title>Active inhibitor-1 maintains protein hyper-phosphorylation in aging hearts and halts remodeling in failing hearts</title><source>PubMed Central (Open access)</source><source>MEDLINE</source><source>Public Library of Science</source><source>DOAJ Directory of Open Access Journals</source><source>Free Full-Text Journals in Chemistry</source><source>EZB Electronic Journals Library</source><creator>Pritchard, Tracy J ; Kawase, Yoshiaki ; Haghighi, Kobra ; Anjak, Ahmad ; Cai, Wenfeng ; Jiang, Min ; Nicolaou, Persoulla ; Pylar, George ; Karakikes, Ioannis ; Rapti, Kleopatra ; Rubinstein, Jack ; Hajjar, Roger J ; Kranias, Evangelia G</creator><contributor>Sussman, Mark A.</contributor><creatorcontrib>Pritchard, Tracy J ; Kawase, Yoshiaki ; Haghighi, Kobra ; Anjak, Ahmad ; Cai, Wenfeng ; Jiang, Min ; Nicolaou, Persoulla ; Pylar, George ; Karakikes, Ioannis ; Rapti, Kleopatra ; Rubinstein, Jack ; Hajjar, Roger J ; Kranias, Evangelia G ; Sussman, Mark A.</creatorcontrib><description>Impaired sarcoplasmic reticulum calcium cycling and depressed contractility are key characteristics in heart failure. Defects in sarcoplasmic reticulum function are characterized by decreased SERCA2a Ca-transport that is partially attributable to dephosphorylation of its regulator phospholamban by increased protein phosphatase 1 activity. Inhibition of protein phosphatase 1 through activation of its endogenous inhibitor-1 has been shown to enhance cardiac Ca-handling and contractility as well as protect from pathological stress remodeling in young mice. In this study, we assessed the long-term effects of inducible expression of constitutively active inhibitor-1 in the adult heart and followed function and remodeling through the aging process, up to 20 months. Mice with inhibitor-1 had normal survival and similar function to WTs. There was no overt remodeling as evidenced by measures of left ventricular end-systolic and diastolic diameters and posterior wall dimensions, heart weight to tibia length ratio, and histology. Higher phosphorylation of phospholamban at both Ser16 and Thr17 was maintained in aged hearts with active inhibitor-1, potentially offsetting the effects of elevated Ser2815-phosphorylation in ryanodine receptor, as there were no increases in arrhythmias under stress conditions in 20-month old mice. Furthermore, long-term expression of active inhibitor-1 via recombinant adeno-associated virus type 9 gene transfer in rats with pressure-overload induced heart failure improved function and prevented remodeling, associated with increased phosphorylation of phospholamban at Ser16 and Thr17. Thus, chronic inhibition of protein phosphatase 1, through increases in active inhibitor-1, does not accelerate age-related cardiomyopathy and gene transfer of this molecule in vivo improves function and halts remodeling in the long term.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0080717</identifier><identifier>PMID: 24312496</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Aging ; Aging - genetics ; Aging - metabolism ; Aging - pathology ; Animals ; Biophysics ; Ca2+-transporting ATPase ; Calcium ; Calcium (reticular) ; Calcium - metabolism ; Calcium-Binding Proteins - genetics ; Calcium-Binding Proteins - metabolism ; Cardiac muscle ; Cardiomyopathies - genetics ; Cardiomyopathies - metabolism ; Cardiomyopathies - pathology ; Cardiomyopathy ; Defects ; Dephosphorylation ; Enzyme inhibitors ; Gene expression ; Gene transfer ; Health aspects ; Heart ; Heart diseases ; Heart failure ; Heart Failure - genetics ; Heart Failure - metabolism ; Heart Failure - pathology ; Histology ; Inhibition ; Inhibitors ; Internal medicine ; Kinases ; Laboratory animals ; Long-term effects ; Medicine ; Mice ; Mice, Transgenic ; Muscle contraction ; Myocardium - metabolism ; Myocardium - pathology ; Pharmacology ; Phosphatase ; Phosphatases ; Phospholamban ; Phosphoprotein phosphatase ; Phosphorylation ; Phosphorylation - genetics ; Physiological aspects ; Physiology ; Protein phosphatase ; Proteins ; Proteins - genetics ; Proteins - metabolism ; Rats ; Remodeling ; Rodents ; Sarcoplasmic reticulum ; Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics ; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism ; Tibia ; Ventricle ; Ventricular Remodeling ; Viruses</subject><ispartof>PloS one, 2013-12, Vol.8 (12), p.e80717-e80717</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Pritchard et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/3.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Pritchard et al 2013 Pritchard et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-941d79ff7133c513f75f855283b9fe172ea0d0e5a8126e3fc9d79534ed4329a93</citedby><cites>FETCH-LOGICAL-c692t-941d79ff7133c513f75f855283b9fe172ea0d0e5a8126e3fc9d79534ed4329a93</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3846572/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3846572/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,728,781,785,865,886,2103,2929,23868,27926,27927,53793,53795</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24312496$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Sussman, Mark A.</contributor><creatorcontrib>Pritchard, Tracy J</creatorcontrib><creatorcontrib>Kawase, Yoshiaki</creatorcontrib><creatorcontrib>Haghighi, Kobra</creatorcontrib><creatorcontrib>Anjak, Ahmad</creatorcontrib><creatorcontrib>Cai, Wenfeng</creatorcontrib><creatorcontrib>Jiang, Min</creatorcontrib><creatorcontrib>Nicolaou, Persoulla</creatorcontrib><creatorcontrib>Pylar, George</creatorcontrib><creatorcontrib>Karakikes, Ioannis</creatorcontrib><creatorcontrib>Rapti, Kleopatra</creatorcontrib><creatorcontrib>Rubinstein, Jack</creatorcontrib><creatorcontrib>Hajjar, Roger J</creatorcontrib><creatorcontrib>Kranias, Evangelia G</creatorcontrib><title>Active inhibitor-1 maintains protein hyper-phosphorylation in aging hearts and halts remodeling in failing hearts</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Impaired sarcoplasmic reticulum calcium cycling and depressed contractility are key characteristics in heart failure. Defects in sarcoplasmic reticulum function are characterized by decreased SERCA2a Ca-transport that is partially attributable to dephosphorylation of its regulator phospholamban by increased protein phosphatase 1 activity. Inhibition of protein phosphatase 1 through activation of its endogenous inhibitor-1 has been shown to enhance cardiac Ca-handling and contractility as well as protect from pathological stress remodeling in young mice. In this study, we assessed the long-term effects of inducible expression of constitutively active inhibitor-1 in the adult heart and followed function and remodeling through the aging process, up to 20 months. Mice with inhibitor-1 had normal survival and similar function to WTs. There was no overt remodeling as evidenced by measures of left ventricular end-systolic and diastolic diameters and posterior wall dimensions, heart weight to tibia length ratio, and histology. Higher phosphorylation of phospholamban at both Ser16 and Thr17 was maintained in aged hearts with active inhibitor-1, potentially offsetting the effects of elevated Ser2815-phosphorylation in ryanodine receptor, as there were no increases in arrhythmias under stress conditions in 20-month old mice. Furthermore, long-term expression of active inhibitor-1 via recombinant adeno-associated virus type 9 gene transfer in rats with pressure-overload induced heart failure improved function and prevented remodeling, associated with increased phosphorylation of phospholamban at Ser16 and Thr17. Thus, chronic inhibition of protein phosphatase 1, through increases in active inhibitor-1, does not accelerate age-related cardiomyopathy and gene transfer of this molecule in vivo improves function and halts remodeling in the long term.</description><subject>Aging</subject><subject>Aging - genetics</subject><subject>Aging - metabolism</subject><subject>Aging - pathology</subject><subject>Animals</subject><subject>Biophysics</subject><subject>Ca2+-transporting ATPase</subject><subject>Calcium</subject><subject>Calcium (reticular)</subject><subject>Calcium - metabolism</subject><subject>Calcium-Binding Proteins - genetics</subject><subject>Calcium-Binding Proteins - metabolism</subject><subject>Cardiac muscle</subject><subject>Cardiomyopathies - genetics</subject><subject>Cardiomyopathies - metabolism</subject><subject>Cardiomyopathies - pathology</subject><subject>Cardiomyopathy</subject><subject>Defects</subject><subject>Dephosphorylation</subject><subject>Enzyme inhibitors</subject><subject>Gene expression</subject><subject>Gene transfer</subject><subject>Health aspects</subject><subject>Heart</subject><subject>Heart diseases</subject><subject>Heart failure</subject><subject>Heart Failure - genetics</subject><subject>Heart Failure - metabolism</subject><subject>Heart Failure - pathology</subject><subject>Histology</subject><subject>Inhibition</subject><subject>Inhibitors</subject><subject>Internal medicine</subject><subject>Kinases</subject><subject>Laboratory animals</subject><subject>Long-term effects</subject><subject>Medicine</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Muscle contraction</subject><subject>Myocardium - metabolism</subject><subject>Myocardium - pathology</subject><subject>Pharmacology</subject><subject>Phosphatase</subject><subject>Phosphatases</subject><subject>Phospholamban</subject><subject>Phosphoprotein phosphatase</subject><subject>Phosphorylation</subject><subject>Phosphorylation - genetics</subject><subject>Physiological aspects</subject><subject>Physiology</subject><subject>Protein phosphatase</subject><subject>Proteins</subject><subject>Proteins - genetics</subject><subject>Proteins - metabolism</subject><subject>Rats</subject><subject>Remodeling</subject><subject>Rodents</subject><subject>Sarcoplasmic reticulum</subject><subject>Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics</subject><subject>Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism</subject><subject>Tibia</subject><subject>Ventricle</subject><subject>Ventricular Remodeling</subject><subject>Viruses</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNk1uLnDAUx6W0dC_tNyitUCjtg1NzU_NSGJZeBhYWensNGU00Q0zcJC6db79xx92OZR-qBA_J7__PSTwnSV6BfAVQCT7u7OgM16vBGrHK8yovQfkkOQUUwayAOXp6FJ8kZ97v8pygqiieJycQIwAxLU6T63Ud1I1IlenUVgXrMpD2XJkQh08HZ4NQJu32g3DZ0Fkfh9trHpQ1UZPyVpk27QR3wafcNGnHdYyc6G0j9LQWIcmV_ou9SJ5Jrr14OX_Pk19fPv-8-JZdXn3dXKwvs7qgMGQUg6akUpYAoZoAJEsiK0JghbZUClBCwfMmF4RXABYCyZpGnCAsGowg5RSdJ28OvoO2ns235RnABcoprshEbA5EY_mODU713O2Z5YrdTVjXspiwqrVgNMqKSkBCCMAUUV40EGwhR6jCMZTR69O827jtRVMLExzXC9PlilEda-0NmwxICaPB-9nA2etR-MB65WuhNTfCjnd5k6ogAE55v_0Hffx0M9XyeABlpI371pMpW-OywvFBE7V6hIpvI3pVx9KSKs4vBB8WgsgE8Se0fPSebX58_3_26veSfXfExlLRofNWj1Ol-SWID2DtrPdOyIdLBjmbOuP-NtjUGWzujCh7ffyDHkT3rYBuAUaSCLw</recordid><startdate>20131202</startdate><enddate>20131202</enddate><creator>Pritchard, Tracy J</creator><creator>Kawase, Yoshiaki</creator><creator>Haghighi, Kobra</creator><creator>Anjak, Ahmad</creator><creator>Cai, Wenfeng</creator><creator>Jiang, Min</creator><creator>Nicolaou, Persoulla</creator><creator>Pylar, George</creator><creator>Karakikes, Ioannis</creator><creator>Rapti, Kleopatra</creator><creator>Rubinstein, Jack</creator><creator>Hajjar, Roger J</creator><creator>Kranias, Evangelia G</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20131202</creationdate><title>Active inhibitor-1 maintains protein hyper-phosphorylation in aging hearts and halts remodeling in failing hearts</title><author>Pritchard, Tracy J ; Kawase, Yoshiaki ; Haghighi, Kobra ; Anjak, Ahmad ; Cai, Wenfeng ; Jiang, Min ; Nicolaou, Persoulla ; Pylar, George ; Karakikes, Ioannis ; Rapti, Kleopatra ; Rubinstein, Jack ; Hajjar, Roger J ; Kranias, Evangelia G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c692t-941d79ff7133c513f75f855283b9fe172ea0d0e5a8126e3fc9d79534ed4329a93</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Aging</topic><topic>Aging - genetics</topic><topic>Aging - metabolism</topic><topic>Aging - pathology</topic><topic>Animals</topic><topic>Biophysics</topic><topic>Ca2+-transporting ATPase</topic><topic>Calcium</topic><topic>Calcium (reticular)</topic><topic>Calcium - metabolism</topic><topic>Calcium-Binding Proteins - genetics</topic><topic>Calcium-Binding Proteins - metabolism</topic><topic>Cardiac muscle</topic><topic>Cardiomyopathies - genetics</topic><topic>Cardiomyopathies - metabolism</topic><topic>Cardiomyopathies - pathology</topic><topic>Cardiomyopathy</topic><topic>Defects</topic><topic>Dephosphorylation</topic><topic>Enzyme inhibitors</topic><topic>Gene expression</topic><topic>Gene transfer</topic><topic>Health aspects</topic><topic>Heart</topic><topic>Heart diseases</topic><topic>Heart failure</topic><topic>Heart Failure - genetics</topic><topic>Heart Failure - metabolism</topic><topic>Heart Failure - pathology</topic><topic>Histology</topic><topic>Inhibition</topic><topic>Inhibitors</topic><topic>Internal medicine</topic><topic>Kinases</topic><topic>Laboratory animals</topic><topic>Long-term effects</topic><topic>Medicine</topic><topic>Mice</topic><topic>Mice, Transgenic</topic><topic>Muscle contraction</topic><topic>Myocardium - metabolism</topic><topic>Myocardium - pathology</topic><topic>Pharmacology</topic><topic>Phosphatase</topic><topic>Phosphatases</topic><topic>Phospholamban</topic><topic>Phosphoprotein phosphatase</topic><topic>Phosphorylation</topic><topic>Phosphorylation - genetics</topic><topic>Physiological aspects</topic><topic>Physiology</topic><topic>Protein phosphatase</topic><topic>Proteins</topic><topic>Proteins - genetics</topic><topic>Proteins - metabolism</topic><topic>Rats</topic><topic>Remodeling</topic><topic>Rodents</topic><topic>Sarcoplasmic reticulum</topic><topic>Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics</topic><topic>Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism</topic><topic>Tibia</topic><topic>Ventricle</topic><topic>Ventricular Remodeling</topic><topic>Viruses</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pritchard, Tracy J</creatorcontrib><creatorcontrib>Kawase, Yoshiaki</creatorcontrib><creatorcontrib>Haghighi, Kobra</creatorcontrib><creatorcontrib>Anjak, Ahmad</creatorcontrib><creatorcontrib>Cai, Wenfeng</creatorcontrib><creatorcontrib>Jiang, Min</creatorcontrib><creatorcontrib>Nicolaou, Persoulla</creatorcontrib><creatorcontrib>Pylar, George</creatorcontrib><creatorcontrib>Karakikes, Ioannis</creatorcontrib><creatorcontrib>Rapti, Kleopatra</creatorcontrib><creatorcontrib>Rubinstein, Jack</creatorcontrib><creatorcontrib>Hajjar, Roger J</creatorcontrib><creatorcontrib>Kranias, Evangelia G</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale in Context: Opposing Viewpoints</collection><collection>Gale in Context: Science</collection><collection>ProQuest Central (Corporate)</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Biotechnology Research Abstracts</collection><collection>Proquest Nursing & Allied Health Source</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Meteorological & Geoastrophysical Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Agricultural Science Collection</collection><collection>Health & Medical Collection (Proquest)</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Materials Science & Engineering Collection</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central UK/Ireland</collection><collection>Advanced Technologies & Aerospace Database (1962 - current)</collection><collection>ProQuest Agriculture & Environmental Science Database</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Technology Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>ProQuest Materials Science Collection</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection (Proquest) (PQ_SDU_P3)</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Materials Science Database</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Meteorological & Geoastrophysical Abstracts - Academic</collection><collection>ProQuest Engineering Collection</collection><collection>ProQuest Biological Science Collection</collection><collection>Agriculture Science Database</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>ProQuest Biological Science Journals</collection><collection>ProQuest Engineering Database</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials science collection</collection><collection>Publicly Available Content Database (Proquest) (PQ_SDU_P3)</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>Engineering collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Pritchard, Tracy J</au><au>Kawase, Yoshiaki</au><au>Haghighi, Kobra</au><au>Anjak, Ahmad</au><au>Cai, Wenfeng</au><au>Jiang, Min</au><au>Nicolaou, Persoulla</au><au>Pylar, George</au><au>Karakikes, Ioannis</au><au>Rapti, Kleopatra</au><au>Rubinstein, Jack</au><au>Hajjar, Roger J</au><au>Kranias, Evangelia G</au><au>Sussman, Mark A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Active inhibitor-1 maintains protein hyper-phosphorylation in aging hearts and halts remodeling in failing hearts</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-12-02</date><risdate>2013</risdate><volume>8</volume><issue>12</issue><spage>e80717</spage><epage>e80717</epage><pages>e80717-e80717</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Impaired sarcoplasmic reticulum calcium cycling and depressed contractility are key characteristics in heart failure. Defects in sarcoplasmic reticulum function are characterized by decreased SERCA2a Ca-transport that is partially attributable to dephosphorylation of its regulator phospholamban by increased protein phosphatase 1 activity. Inhibition of protein phosphatase 1 through activation of its endogenous inhibitor-1 has been shown to enhance cardiac Ca-handling and contractility as well as protect from pathological stress remodeling in young mice. In this study, we assessed the long-term effects of inducible expression of constitutively active inhibitor-1 in the adult heart and followed function and remodeling through the aging process, up to 20 months. Mice with inhibitor-1 had normal survival and similar function to WTs. There was no overt remodeling as evidenced by measures of left ventricular end-systolic and diastolic diameters and posterior wall dimensions, heart weight to tibia length ratio, and histology. Higher phosphorylation of phospholamban at both Ser16 and Thr17 was maintained in aged hearts with active inhibitor-1, potentially offsetting the effects of elevated Ser2815-phosphorylation in ryanodine receptor, as there were no increases in arrhythmias under stress conditions in 20-month old mice. Furthermore, long-term expression of active inhibitor-1 via recombinant adeno-associated virus type 9 gene transfer in rats with pressure-overload induced heart failure improved function and prevented remodeling, associated with increased phosphorylation of phospholamban at Ser16 and Thr17. Thus, chronic inhibition of protein phosphatase 1, through increases in active inhibitor-1, does not accelerate age-related cardiomyopathy and gene transfer of this molecule in vivo improves function and halts remodeling in the long term.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24312496</pmid><doi>10.1371/journal.pone.0080717</doi><tpages>e80717</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2013-12, Vol.8 (12), p.e80717-e80717 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1463094859 |
| source | PubMed Central (Open access); MEDLINE; Public Library of Science; DOAJ Directory of Open Access Journals; Free Full-Text Journals in Chemistry; EZB Electronic Journals Library |
| subjects | Aging Aging - genetics Aging - metabolism Aging - pathology Animals Biophysics Ca2+-transporting ATPase Calcium Calcium (reticular) Calcium - metabolism Calcium-Binding Proteins - genetics Calcium-Binding Proteins - metabolism Cardiac muscle Cardiomyopathies - genetics Cardiomyopathies - metabolism Cardiomyopathies - pathology Cardiomyopathy Defects Dephosphorylation Enzyme inhibitors Gene expression Gene transfer Health aspects Heart Heart diseases Heart failure Heart Failure - genetics Heart Failure - metabolism Heart Failure - pathology Histology Inhibition Inhibitors Internal medicine Kinases Laboratory animals Long-term effects Medicine Mice Mice, Transgenic Muscle contraction Myocardium - metabolism Myocardium - pathology Pharmacology Phosphatase Phosphatases Phospholamban Phosphoprotein phosphatase Phosphorylation Phosphorylation - genetics Physiological aspects Physiology Protein phosphatase Proteins Proteins - genetics Proteins - metabolism Rats Remodeling Rodents Sarcoplasmic reticulum Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism Tibia Ventricle Ventricular Remodeling Viruses |
| title | Active inhibitor-1 maintains protein hyper-phosphorylation in aging hearts and halts remodeling in failing hearts |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-17T21%3A47%3A06IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Active%20inhibitor-1%20maintains%20protein%20hyper-phosphorylation%20in%20aging%20hearts%20and%20halts%20remodeling%20in%20failing%20hearts&rft.jtitle=PloS%20one&rft.au=Pritchard,%20Tracy%20J&rft.date=2013-12-02&rft.volume=8&rft.issue=12&rft.spage=e80717&rft.epage=e80717&rft.pages=e80717-e80717&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0080717&rft_dat=%3Cgale_plos_%3EA478444439%3C/gale_plos_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1463094859&rft_id=info:pmid/24312496&rft_galeid=A478444439&rft_doaj_id=oai_doaj_org_article_914668e255514939a6d21b2a33846d2f&rfr_iscdi=true |