Mutation in integrin-linked kinase (ILK(R211A)) and heat-shock protein 70 comprise a broadly cardioprotective complex.
RATIONALE: Integrin-linked kinase (ILK) has been proposed as a novel molecular target that has translational potential in diverse cardiac diseases, since its upregulation promotes a broadly cardioprotective phenotype. However, ILK has been implicated as both a cardioprotective and oncogenic target,...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3832499?pdf=render |
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| author | Alexandra Traister Mark Walsh Shabana Aafaqi Mingliang Lu Xiaojing Dai Mark R Henkleman Abdul Momen Yu-Quing Zhou Mansoor Husain Sara Arab Sara Piran Gregory Hannigan John G Coles |
| author_facet | Alexandra Traister Mark Walsh Shabana Aafaqi Mingliang Lu Xiaojing Dai Mark R Henkleman Abdul Momen Yu-Quing Zhou Mansoor Husain Sara Arab Sara Piran Gregory Hannigan John G Coles |
| author_sort | Alexandra Traister |
| collection | DOAJ |
| description | RATIONALE: Integrin-linked kinase (ILK) has been proposed as a novel molecular target that has translational potential in diverse cardiac diseases, since its upregulation promotes a broadly cardioprotective phenotype. However, ILK has been implicated as both a cardioprotective and oncogenic target, which imposes therapeutic constraints that are generally relevant to the translational potential of many kinases. OBJECTIVE: To study the cardioprotective properties of the activation-resistant, non-oncogenic, mutation of ILK (ILK(R211A)) against experimental MI in vivo and Doxorubicin induced apoptosis in vitro and it's relationships to stress induced heat shock proteins. METHODS/RESULTS: The transgenic mouse heart over-expressing a point mutation in the ILK pleckstrin homology (PH) domain (Tg(R211A)) exhibits a highly cardioprotective phenotype based on LAD-ligation-induced MI reduction in vivo, and on protection against doxorubicin (DOX)-induced cardiomyocyte apoptosis when overexpressed in human induced pluripotent stem cell (iPS)-derived cardiomyocytes in vitro. Intriguingly, the degree of cardioprotection seen with the ILK(R211A) mutation exceeded that with the ILK(S343D) mutation. Microarray and immunoprecipitation analyses revealed upregulation of expression levels and specific binding of ILK(WT), ILK(S343D) and ILK(R211A) to both constitutively active heat-shock protein 70 (Hsc70) and inducible Hsp70 in response to MI, and to acute ILK overexpression in iPSC-cardiomyocytes. ILK-mediated cardioprotection was shown to depend upon Hsp70 ATPase activity. CONCLUSIONS: These findings indicate that wild type ILK and the non-oncogenic ILK(R211A) mutation comprise a cardioprotective module with Hsp/c70. These results advance a novel target discovery theme in which kinase mutations can be safely engineered to enhance cardioprotective effects. |
| first_indexed | 2024-12-23T13:25:05Z |
| format | Article |
| id | doaj.art-b9c34c210c244135b63de52b9650e603 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-23T13:25:05Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-b9c34c210c244135b63de52b9650e6032022-12-21T17:45:19ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-01811e7733110.1371/journal.pone.0077331Mutation in integrin-linked kinase (ILK(R211A)) and heat-shock protein 70 comprise a broadly cardioprotective complex.Alexandra TraisterMark WalshShabana AafaqiMingliang LuXiaojing DaiMark R HenklemanAbdul MomenYu-Quing ZhouMansoor HusainSara ArabSara PiranGregory HanniganJohn G ColesRATIONALE: Integrin-linked kinase (ILK) has been proposed as a novel molecular target that has translational potential in diverse cardiac diseases, since its upregulation promotes a broadly cardioprotective phenotype. However, ILK has been implicated as both a cardioprotective and oncogenic target, which imposes therapeutic constraints that are generally relevant to the translational potential of many kinases. OBJECTIVE: To study the cardioprotective properties of the activation-resistant, non-oncogenic, mutation of ILK (ILK(R211A)) against experimental MI in vivo and Doxorubicin induced apoptosis in vitro and it's relationships to stress induced heat shock proteins. METHODS/RESULTS: The transgenic mouse heart over-expressing a point mutation in the ILK pleckstrin homology (PH) domain (Tg(R211A)) exhibits a highly cardioprotective phenotype based on LAD-ligation-induced MI reduction in vivo, and on protection against doxorubicin (DOX)-induced cardiomyocyte apoptosis when overexpressed in human induced pluripotent stem cell (iPS)-derived cardiomyocytes in vitro. Intriguingly, the degree of cardioprotection seen with the ILK(R211A) mutation exceeded that with the ILK(S343D) mutation. Microarray and immunoprecipitation analyses revealed upregulation of expression levels and specific binding of ILK(WT), ILK(S343D) and ILK(R211A) to both constitutively active heat-shock protein 70 (Hsc70) and inducible Hsp70 in response to MI, and to acute ILK overexpression in iPSC-cardiomyocytes. ILK-mediated cardioprotection was shown to depend upon Hsp70 ATPase activity. CONCLUSIONS: These findings indicate that wild type ILK and the non-oncogenic ILK(R211A) mutation comprise a cardioprotective module with Hsp/c70. These results advance a novel target discovery theme in which kinase mutations can be safely engineered to enhance cardioprotective effects.http://europepmc.org/articles/PMC3832499?pdf=render |
| spellingShingle | Alexandra Traister Mark Walsh Shabana Aafaqi Mingliang Lu Xiaojing Dai Mark R Henkleman Abdul Momen Yu-Quing Zhou Mansoor Husain Sara Arab Sara Piran Gregory Hannigan John G Coles Mutation in integrin-linked kinase (ILK(R211A)) and heat-shock protein 70 comprise a broadly cardioprotective complex. PLoS ONE |
| title | Mutation in integrin-linked kinase (ILK(R211A)) and heat-shock protein 70 comprise a broadly cardioprotective complex. |
| title_full | Mutation in integrin-linked kinase (ILK(R211A)) and heat-shock protein 70 comprise a broadly cardioprotective complex. |
| title_fullStr | Mutation in integrin-linked kinase (ILK(R211A)) and heat-shock protein 70 comprise a broadly cardioprotective complex. |
| title_full_unstemmed | Mutation in integrin-linked kinase (ILK(R211A)) and heat-shock protein 70 comprise a broadly cardioprotective complex. |
| title_short | Mutation in integrin-linked kinase (ILK(R211A)) and heat-shock protein 70 comprise a broadly cardioprotective complex. |
| title_sort | mutation in integrin linked kinase ilk r211a and heat shock protein 70 comprise a broadly cardioprotective complex |
| url | http://europepmc.org/articles/PMC3832499?pdf=render |
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