Document Detail

Endogenous thrombospondin 1 protects the pressure-overloaded myocardium by modulating fibroblast phenotype and matrix metabolism.
MedLine Citation:
PMID:  21947471     Owner:  NLM     Status:  MEDLINE    
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.
Ying Xia; Marcin Dobaczewski; Carlos Gonzalez-Quesada; Wei Chen; Anna Biernacka; Na Li; Dong-Wook Lee; Nikolaos G Frangogiannis
Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-09-26
Journal Detail:
Title:  Hypertension     Volume:  58     ISSN:  1524-4563     ISO Abbreviation:  Hypertension     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-10-21     Completed Date:  2011-12-15     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  7906255     Medline TA:  Hypertension     Country:  United States    
Other Details:
Languages:  eng     Pagination:  902-11     Citation Subset:  IM    
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MeSH Terms
Blotting, Western
Cardiomegaly / physiopathology*
Disease Models, Animal
Extracellular Matrix / genetics,  metabolism*
Hypertension / metabolism,  physiopathology*
Matrix Metalloproteinase 9 / metabolism
Mice, Inbred C57BL
Mice, Knockout
Myofibroblasts / cytology*,  metabolism
RNA, Messenger / metabolism
Random Allocation
Sensitivity and Specificity
Thrombospondin 1 / metabolism*
Ventricular Remodeling
Grant Support
R01 HL-76246/HL/NHLBI NIH HHS; R01 HL-85440/HL/NHLBI NIH HHS; R01 HL076246/HL/NHLBI NIH HHS; R01 HL076246-06/HL/NHLBI NIH HHS; R01 HL076246-07/HL/NHLBI NIH HHS; R01 HL085440/HL/NHLBI NIH HHS; R01 HL085440-04/HL/NHLBI NIH HHS
Reg. No./Substance:
0/RNA, Messenger; 0/Thrombospondin 1; EC Metalloproteinase 9
Comment In:
Hypertension. 2011 Nov;58(5):770-1   [PMID:  21947464 ]

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