| Endogenous thrombospondin 1 protects the pressure-overloaded myocardium by modulating fibroblast phenotype and matrix metabolism. | |
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MedLine Citation:
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PMID: 21947471 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The matricellular protein thrombospondin (TSP) 1 is induced after tissue injury and may regulate reparative responses by activating transforming growth factor-β, by suppressing angiogenesis and by modulating inflammation and matrix metabolism. We hypothesized that endogenous TSP-1 may be involved in the pathogenesis of cardiac remodeling in the pressure-overloaded heart. Myocardial TSP-1 expression was increased in a mouse model of pressure overload because of transverse aortic constriction. TSP-1(-/-) mice exhibited increased early hypertrophy and enhanced late dilation in response to pressure overload. Pressure-overloaded TSP-1 null mice had intense degenerative cardiomyocyte changes, exhibiting more extensive sarcomeric loss and sarcolemmal disruption when compared with wild-type hearts. Accentuated hypertrophy and cardiomyocyte injury in TSP-1(-/-) hearts was accompanied by increased myofibroblast density. However, despite a 2-fold higher infiltration of the cardiac interstitium with myofibroblasts, pressure-overloaded TSP-1 null hearts did not exhibit significantly increased collagen content when compared with wild-type hearts. The disproportionately low collagen content in TSP-1 null hearts was attributed to infiltration with abundant, but functionally defective, fibroblasts that exhibited impaired myofibroblast differentiation and reduced collagen expression in comparison with wild-type fibroblasts. Impaired myofibroblast activation in TSP-1 null hearts was associated with reduced Smad2 phosphorylation reflecting defective transforming growth factor-β signaling. Moreover, TSP-1 null hearts had increased myocardial matrix metalloproteinase 3 expression and enhanced matrix metalloproteinase 9 activation after pressure overload. TSP-1 upregulation in the pressure-overloaded heart critically regulates fibroblast phenotype and matrix remodeling by activating transforming growth factor-β signaling and by promoting matrix preservation, thus preventing chamber dilation. |
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Authors:
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Ying Xia; Marcin Dobaczewski; Carlos Gonzalez-Quesada; Wei Chen; Anna Biernacka; Na Li; Dong-Wook Lee; Nikolaos G Frangogiannis |
Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-09-26 |
Journal Detail:
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Title: Hypertension Volume: 58 ISSN: 1524-4563 ISO Abbreviation: Hypertension Publication Date: 2011 Nov |
Date Detail:
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Created Date: 2011-10-21 Completed Date: 2011-12-15 Revised Date: 2012-01-16 |
Medline Journal Info:
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Nlm Unique ID: 7906255 Medline TA: Hypertension Country: United States |
Other Details:
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Languages: eng Pagination: 902-11 Citation Subset: IM |
Affiliation:
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Wilf Family Cardiovascular Research Institute, Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Blotting, Western Cardiomegaly / physiopathology* Disease Models, Animal Extracellular Matrix / genetics, metabolism* Female Hypertension / metabolism, physiopathology* Male Matrix Metalloproteinase 9 / metabolism Mice Mice, Inbred C57BL Mice, Knockout Myofibroblasts / cytology*, metabolism Phenotype RNA, Messenger / metabolism Random Allocation Sensitivity and Specificity Thrombospondin 1 / metabolism* Up-Regulation Ventricular Remodeling |
| Grant Support | |
ID/Acronym/Agency:
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R01 HL-76246/HL/NHLBI NIH HHS; R01 HL-85440/HL/NHLBI NIH HHS; R01 HL076246-06/HL/NHLBI NIH HHS; R01 HL076246-07/HL/NHLBI NIH HHS; R01 HL076246-08/HL/NHLBI NIH HHS; R01 HL085440-04/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/RNA, Messenger; 0/Thrombospondin 1; EC 3.4.24.35/Matrix Metalloproteinase 9 |
| Comments/Corrections | |
Comment In:
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Hypertension. 2011 Nov;58(5):770-1
[PMID:
21947464
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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