Combined therapy with cardioprotective cytokine administration and antiapoptotic gene transfer in postinfarction heart failure

Okada H, Takemura G, Kosai K, Tsujimoto A, Esaki M, Takahashi T, Nagano S, Kanamori H, Miyata S, Li Y, Ohno T, Maruyama R, Ogino A, Li L, Nakagawa M, Nagashima K, Fujiwara T, Fujiwara H, Minatoguchi S. Combined therapy with cardioprotective cytokine administration and antiapoptotic gene transfer in postinfarction heart failure. Am J Physiol Heart Circ Physiol 296: H616-H626, 2009. First published January 16, 2009; doi:10.1152/ajpheart.01147.2008.-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.