title: Lumican-null mice are susceptible to aging and isoproterenol-induced myocardial fibrosis.
abstract: With aging and stress, the myocardium undergoes structural remodeling, often leading to fibrosis. The purpose of this study is to examine whether lumican, one of the class II small leucine-rich proteoglycans, has a protective role in cardiac remodeling and fibrosis. In attempts to elucidate the hypothesis that lumican may have a protective role in cardiac remodeling and fibrosis, we compared the cardiac phenotypes of young (3-month-old) and elder (6-month- and 12-month-old) lumican-null (Lum-/-) mice. Extra-cellular matrix remodeling and apoptosis are examined to determine the roles of lumican on age-dependent cardiac fibrosis induced by isoproterenol. Compared to wild type littermates, Lum-/-mice exhibited higher mortality due to significantly impaired systolic function, which was associated with an increase of atrial natriuretic peptide (ANP) secreted by the ventricles in response to excessive stretching of myocytes. Masson's Trichrome and silver stains showed significantly more severe ventricle fibrosis in Lum-/-mice. Interestingly, rate of cell death mediated via apoptosis illustrated by the expression of caspase 3 and TUNEL assay was lower in Lum-/-mice after isoproterenol infusion. In addition, Lum-/-mice exhibited higher levels of TGF-β, collagen I/III, and membrane-type matrix metalloproteinase-1 (MT1-MMP/MMP-14) during cardiac remodeling. This study shows that alternations of lumican might be implicated in the pathogenesis of cardiac fibrosis and suggests lumican as novel targets for cardiac fibrosis therapy. Further studies are required to define the mechanism by which lumican modulates cardiac remodeling.
authors.affiliation: Divisiont of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan; Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University; Taiwan.
authors.forename: Shao-Wei
authors.initials: SW
authors.lastname: Chen
authors.affiliation: The Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.
authors.forename: Ying-Chang
authors.initials: YC
authors.lastname: Tung
authors.affiliation: Department of Pathology, Ophthalmology, Chang Gung Memorial Hospital, Chang Gung University, College of Medicine, Taipei, Taiwan.
authors.forename: Shih-Ming
authors.initials: SM
authors.lastname: Jung
authors.affiliation: Divisiont of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.
authors.forename: Yen
authors.initials: Y
authors.lastname: Chu
authors.affiliation: Divisiont of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan.
authors.forename: Pyng-Jing
authors.initials: PJ
authors.lastname: Lin
authors.affiliation: Crawley Vision Research Center, Department of Ophthalmology, College of Medicine, University of Cincinnati, Cincinnati, OH 5267-0838, USA.
authors.forename: Winston W-Y
authors.initials: WW
authors.lastname: Kao
authors.affiliation: The Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan; Healthcare Center, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan; Heart Failure Center, Department of Internal Medicine, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan. Electronic address: taipei.chu@gmail.com.
authors.forename: Pao-Hsien
authors.initials: PH
authors.lastname: Chu
mesh_terms: D000818:Animals; D017209:Apoptosis; D009320:Atrial Natriuretic Factor / Q000737:chemistry; D053148:Caspase 3 / Q000378:metabolism; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D005355:Fibrosis; D006321:Heart / Q000502:physiology*; D006720:Homozygote; D007545:Isoproterenol / Q000737:chemistry*; D007632:Keratan Sulfate / Q000737:chemistry; D000071234:Lumican / Q000235:genetics* / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D024042:Collagen Type I; D024061:Collagen Type III; D000071234:Lumican; C507096:Mmp14 protein, mouse; D016212:Transforming Growth Factor beta; D009320:Atrial Natriuretic Factor; D007632:Keratan Sulfate; C505409:Casp3 protein, mouse; D053148:Caspase 3; D053511:Matrix Metalloproteinase 14; D007545:Isoproterenol
keywords: Cardiac fibrosis; Cardiac remodeling; Isoproterenol; Lumican; Matrix metalloproteinase