title: Endogenous thrombospondin 1 protects the pressure-overloaded myocardium by modulating fibroblast phenotype and matrix metabolism.
abstract: 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.
authors.affiliation: Wilf Family Cardiovascular Research Institute, Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Xia
authors.forename: Marcin
authors.initials: M
authors.lastname: Dobaczewski
authors.forename: Carlos
authors.initials: C
authors.lastname: Gonzalez-Quesada
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Anna
authors.initials: A
authors.lastname: Biernacka
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Dong-Wook
authors.initials: DW
authors.lastname: Lee
authors.forename: Nikolaos G
authors.initials: NG
authors.lastname: Frangogiannis
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006332:Cardiomegaly / Q000503:physiopathology*; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D012680:Sensitivity and Specificity; D019700:Thrombospondin 1 / Q000378:metabolism*; D015854:Up-Regulation; D020257:Ventricular Remodeling
chemical_list: D012333:RNA, Messenger; D019700:Thrombospondin 1; D020780:Matrix Metalloproteinase 9