title: Postinfarction gene therapy with adenoviral vector expressing decorin mitigates cardiac remodeling and dysfunction.
abstract: The small leucine-rich proteoglycan decorin is a natural inhibitor of transforming growth factor-beta (TGF-beta) and exerts antifibrotic effects in heart and to stimulate skeletal muscle regeneration. We investigated decorin's chronic effects on postinfarction cardiac remodeling and dysfunction. Myocardial infarction (MI) was induced in mice by left coronary artery ligation. An adenoviral vector encoding human decorin (Ad. CAG-decorin) was then injected into the hindlimbs on day 3 post-MI (control, Ad.CAG-LacZ). Four weeks post-MI, the decorin-treated mice showed significant mitigation of the left ventricular dilatation and dysfunction seen in control mice. Although infarct size did not differ between the two groups, the infarcted wall thickness was greater and the segmental length of the infarct was smaller in decorin-treated mice. In addition, cellular components, including myofibroblasts and blood vessels, were more abundant within the infarcted area in decorin-treated mice, and fibrosis was significantly reduced in both the infarcted and noninfarcted areas of the left ventricular wall. Ten days post-MI, there was greater cell proliferation and less apoptosis among granulation tissue cells in the infarcted areas of decorin-treated mice. The treatment, however, did not affect proliferation and apoptosis of salvaged cardiomyocytes. Although decorin gene therapy did not affect TGF-beta1 expression in the infarcted heart, it inhibited Smad2/3 activation (downstream mediators of TGF-beta signaling). In summary, postinfarction decorin gene therapy mitigated cardiac remodeling and dysfunction by altering infarct tissue noncardiomyocyte dynamics and preventing cardiac fibrosis, accompanying inhibition of Smad2/3 activation.
authors.affiliation: Division of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.
authors.forename: Longhu
authors.initials: L
authors.lastname: Li
authors.forename: Hideshi
authors.initials: H
authors.lastname: Okada
authors.forename: Genzou
authors.initials: G
authors.lastname: Takemura
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Kosai
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kanamori
authors.forename: Masayasu
authors.initials: M
authors.lastname: Esaki
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Takahashi
authors.forename: Kazuko
authors.initials: K
authors.lastname: Goto
authors.forename: Akiko
authors.initials: A
authors.lastname: Tsujimoto
authors.forename: Rumi
authors.initials: R
authors.lastname: Maruyama
authors.forename: Itta
authors.initials: I
authors.lastname: Kawamura
authors.forename: Tomonori
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Takeyama
authors.forename: Takako
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Hisayoshi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Shinya
authors.initials: S
authors.lastname: Minatoguchi
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002908:Chronic Disease; D058575:Decorin; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis* / Q000235:genetics; D005355:Fibrosis; D015316:Genetic Therapy; D005822:Genetic Vectors; D006367:HeLa Cells; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D011509:Proteoglycans / Q000096:biosynthesis* / Q000235:genetics; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D013997:Time Factors; D014161:Transduction, Genetic; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D020257:Ventricular Remodeling
chemical_list: C546878:DCN protein, human; C546879:Dcn protein, mouse; D058575:Decorin; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D053773:Transforming Growth Factor beta1