Combined therapy with cardioprotective cytokine administration and antiapoptotic gene transfer in postinfarction heart failure
Combined therapy with cardioprotective cytokine administration and antiapoptotic gene transfer in postinfarction heart failure
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DOI：
10.1152/ajpheart.01147.2008
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发表时间：
2009-03-01
影响因子：
4.8
通讯作者：
Minatoguchi, Shinya
中科院分区：
文献类型：
--
作者：
Okada, Hideshi;Takemura, Genzou;Minatoguchi, Shinya
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.心肌保护性细胞因子联合抗凋亡基因转移治疗梗死后心力衰竭。美国生理学杂志心脏循环生理学296：H616-H626，2009年。首次发表于2009年1月16日; doi：10.1152/ajpheart.01147.2008。我们假设，治疗，抗凋亡可溶性Fas（sFas）基因转移，结合心肌保护细胞因子粒细胞集落刺激因子（G-CSF）的管理，将显着减轻心肌梗死（MI）后的心脏重塑和功能障碍。在结扎小鼠左冠状动脉诱导MI后第3天，开始四种不同的处理：生理盐水注射（C组，n = 26）、G-CSF给药（G组，n = 27）、sFas基因腺病毒转移（F组，n = 26）以及后两者联合（G + F组，n = 26）。MI后4周，G + F组的存活率明显高于C组（96% vs.65%，P < 0.05），心功能也是四组中最好的。在G组中，梗死瘢痕较小，纤维化程度较低，而在F组中，瘢痕较厚，面积没有减少，并含有丰富的肌成纤维细胞和血管细胞; G + F组显示两种表型。G-CSF通过对肉芽组织的抗纤维化和增殖作用对梗死组织动力学产生有益作用;然而，它也产生不良的促凋亡作用，导致梗死瘢痕变薄。sFas似乎抵消了后者的缺点。使用来自梗死组织的培养的肌成纤维细胞的体外研究显示，G-CSF增加了伴随Akt和信号转导子和转录激活子3激活的那些细胞的增殖活性，同时加速Fas介导的凋亡，增加Bcl-2与Bcl-2的比率。结果表明，联合使用G-CSF管理和sFas基因治疗是一个潜在的强大的工具，对MI后心力衰竭。
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.