Combined therapy with cardioprotective cytokine administration and antiapoptotic gene transfer in postinfarction heart failure.
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.
Okada
Hideshi
H
Division of Cardiology, Gifu Univ. Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
Takemura
Genzou
G
Kosai
Ken-Ichiro
K
Tsujimoto
Akiko
A
Esaki
Masayasu
M
Takahashi
Tomoyuki
T
Nagano
Satoshi
S
Kanamori
Hiromitsu
H
Miyata
Shusaku
S
Li
Yiwen
Y
Ohno
Takamasa
T
Maruyama
Rumi
R
Ogino
Atsushi
A
Li
Longhu
L
Nakagawa
Munehiro
M
Nagashima
Kenshi
K
Fujiwara
Takako
T
Fujiwara
Hisayoshi
H
Minatoguchi
Shinya
S
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
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