title: Combined therapy with cardioprotective cytokine administration and antiapoptotic gene transfer in postinfarction heart failure.
abstract: We hypothesized that therapy, composed of antiapoptotic soluble Fas (sFas) gene transfer, combined with administration of the cardioprotective cytokine granulocyte colony-stimulating factor (G-CSF), would markedly mitigate cardiac remodeling and dysfunction following myocardial infarction (MI). On the 3rd day after MI induced by ligating the left coronary artery in mice, four different treatments were initiated: saline injection (Group C, n = 26); G-CSF administration (Group G, n = 27); adenoviral transfer of sFas gene (Group F, n = 26); and the latter two together (Group G+F, n = 26). Four weeks post-MI, Group G+F showed better survival than Group C (96 vs. 65%, P < 0.05) and the best cardiac function among the four groups. In Group G, the infarct scar was smaller and less fibrotic, whereas in Group F the scar was thicker, without a reduction in area, and contained abundant myofibroblasts and vascular cells; Group G+F showed both phenotypes. G-CSF exerted a beneficial effect on infarct tissue dynamics through antifibrotic and proliferative effects on granulation tissue; however, it also exerts an adverse proapoptotic effect that leads to thinning of the infarct scar. sFas appeared to offset the latter drawback. In vitro study using cultured myofibroblasts derived from the infarct tissue revealed that G-CSF increased proliferating activity of those cells accompanying activation of Akt and signal transducer and activator of transcription 3, while accelerating Fas-mediated apoptosis with increasing Bax-to-Bcl-2 ratio. The results suggest that combined use of G-CSF administration and sFas gene therapy is a potentially powerful tool against post-MI heart failure.
authors.affiliation: Division of Cardiology, Gifu Univ. Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
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: Akiko
authors.initials: A
authors.lastname: Tsujimoto
authors.forename: Masayasu
authors.initials: M
authors.lastname: Esaki
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Takahashi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nagano
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kanamori
authors.forename: Shusaku
authors.initials: S
authors.lastname: Miyata
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Li
authors.forename: Takamasa
authors.initials: T
authors.lastname: Ohno
authors.forename: Rumi
authors.initials: R
authors.lastname: Maruyama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ogino
authors.forename: Longhu
authors.initials: L
authors.lastname: Li
authors.forename: Munehiro
authors.initials: M
authors.lastname: Nakagawa
authors.forename: Kenshi
authors.initials: K
authors.lastname: Nagashima
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 / Q000187:drug effects / Q000235:genetics; D002316:Cardiotonic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000473:pathology; D005355:Fibrosis; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D006097:Granulation Tissue / Q000187:drug effects / Q000473:pathology; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D006333:Heart Failure / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D006801:Humans; D000078224:Lenograstim; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000150:complications / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012038:Regeneration / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000235:genetics / Q000473:pathology / Q000628:therapy; D020257:Ventricular Remodeling / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics* / Q000378:metabolism
chemical_list: C494827:Bax protein, mouse; D002316:Cardiotonic Agents; C491899:Fas protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D016179:Granulocyte Colony-Stimulating Factor; D000078224:Lenograstim