| Inducible expression of active protein phosphatase-1 inhibitor-1 enhances basal cardiac function and protects against ischemia/reperfusion injury. | |
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MedLine Citation:
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PMID: 19299645 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Ischemic heart disease, which remains the leading cause of morbidity and mortality in the Western world, is invariably characterized by impaired cardiac function and disturbed Ca(2+) homeostasis. Because enhanced inhibitor-1 (I-1) activity has been suggested to preserve Ca(2+) cycling, we sought to define whether increases in I-1 activity in the adult heart may ameliorate contractile dysfunction and cellular injury in the face of an ischemic insult. To this end, we generated an inducible transgenic mouse model that enabled temporally controlled expression of active I-1 (T35D). Active I-1 expression in the adult heart elicited significant enhancement of contractile function, associated with preferential phospholamban phosphorylation and enhanced sarcoplasmic reticulum Ca(2+)-transport. Further phosphoproteomic analysis revealed alterations in proteins associated with energy production and protein synthesis, possibly to support the increased metabolic demands of the hyperdynamic hearts. Importantly, on ischemia/reperfusion-induced injury, active I-1 expression augmented contractile function and recovery. Further examination revealed that the infarct region and apoptotic as well as necrotic injuries were significantly attenuated by enhanced I-1 activity. These cardioprotective effects were associated with suppression of the endoplasmic reticulum stress response. The present findings indicate that increased I-1 activity in the adult heart enhances Ca(2+) cycling and improves mechanical recovery, as well as cell survival after an ischemic insult, suggesting that active I-1 may represent a potential therapeutic strategy in myocardial infarction. |
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Authors:
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Persoulla Nicolaou; Patricia Rodriguez; Xiaoping Ren; Xiaoyang Zhou; Jiang Qian; Sakthivel Sadayappan; Bryan Mitton; Anand Pathak; Jeffrey Robbins; Roger J Hajjar; Keith Jones; Evangelia G Kranias |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2009-03-19 |
Journal Detail:
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Title: Circulation research Volume: 104 ISSN: 1524-4571 ISO Abbreviation: Circ. Res. Publication Date: 2009 Apr |
Date Detail:
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Created Date: 2009-04-24 Completed Date: 2009-05-07 Revised Date: 2012-10-09 |
Medline Journal Info:
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Nlm Unique ID: 0047103 Medline TA: Circ Res Country: United States |
Other Details:
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Languages: eng Pagination: 1012-20 Citation Subset: IM |
Affiliation:
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Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0575, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis Calcium Signaling Calcium-Binding Proteins / metabolism Disease Models, Animal Endoplasmic Reticulum / metabolism Intracellular Signaling Peptides and Proteins / genetics, metabolism* Mice Mice, Transgenic Mutation Myocardial Contraction* Myocardial Infarction / enzymology, physiopathology, prevention & control* Myocardial Reperfusion Injury / enzymology, physiopathology, prevention & control* Myocardium / enzymology*, pathology Necrosis Phosphorylation Proteomics Recovery of Function Sarcoplasmic Reticulum / metabolism Stress, Physiological Time Factors Up-Regulation Ventricular Function, Left* |
| Grant Support | |
ID/Acronym/Agency:
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HL-26507/HL/NHLBI NIH HHS; HL-64018/HL/NHLBI NIH HHS; HL-77101/HL/NHLBI NIH HHS; P50 HL077101-05/HL/NHLBI NIH HHS; R01 HL026057-28/HL/NHLBI NIH HHS; R01 HL064018-10/HL/NHLBI NIH HHS; R01 HL083156-03/HL/NHLBI NIH HHS; R01 HL088434/HL/NHLBI NIH HHS; R01 HL088434-03/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Calcium-Binding Proteins; 0/Intracellular Signaling Peptides and Proteins; 0/phospholamban; 0/protein phosphatase inhibitor-1 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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