Cardiomyocyte-specific Bcl-2 overexpression attenuates ischemia-reperfusion injury, immune response during acute rejection, and graft coronary artery disease
Cardiomyocyte-specific Bcl-2 overexpression attenuates ischemia-reperfusion injury, immune response during acute rejection, and graft coronary artery disease
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DOI：
10.1182/blood-2004-02-0666
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发表时间：
2004-12-01
期刊：
影响因子：
20.3
通讯作者：
Robbins, RC
中科院分区：
文献类型：
--
作者：
Tanaka, M;Nakae, S;Robbins, RC
心脏移植后，移植物损伤继发于缺血再灌注损伤和急性排斥反应。这种损伤最终导致移植物冠状动脉疾病（GCAD）的发展，这限制了移植物的长期存活。细胞凋亡直接参与移植物损伤，促进GCAD的发展。为了评估抗凋亡因子Bcl-2在GCAD过程中的作用，我们将在α-肌球蛋白重链启动子控制下过表达人Bcl-2的FVB转基因小鼠的心脏移植到同种异体C57 BL/6小鼠中。Bcl-2过表达导致细胞色素C介导的caspase-9依赖的心肌细胞凋亡和局部炎症减少在心脏移植物缺血再灌注损伤过程中，中性粒细胞浸润和促炎细胞因子的产生，（炎性细胞浸润，T（H）1细胞因子和趋化因子的产生，和粘附分子的表达）而不影响宿主脾脏中的CD 4（+）和CD 8（+）细胞应答。因此，局部Bcl-2表达直接有助于调节同种异体移植排斥反应中的局部免疫应答，导致GCAD减弱。总之，我们的研究结果表明，Bcl-2表达的药理上调或基因转移的调制可能是心脏移植物的短期和长期功能的临床效益。
After cardiac transplantation, graft damage occurs secondary to ischemia-reperfusion injury and acute rejection. This damage ultimately leads to the development of graft coronary artery disease (GCAD), which limits long-term graft survival. Apoptosis is directly involved in graft injury, contributing to the development of GCAD. To assess the role of the antiapoptotic factor Bcl-2 in the process of GCAD, we transplanted hearts from FVB transgenic mice overexpressing human Bcl-2 under the control of alpha-myosin heavy chain promoter into allogenic C57BL/6 mice. Bcl-2 overexpression led to reduced cytochrome c-mediated caspase-9-dependent cardiomyocyte apoptosis and local inflammation (neutrophil infiltration and proinflammatory cytokine production) in cardiac allografts during ischemia-reperfusion injury and also led to reduced immune responses (inflammatory cell infiltration, production of T(H)1 cytokines and chemokines, and expression of adhesion molecules) during acute and chronic rejection without affecting host CD4(+) and CD8(+) cell responses in the spleen. Thus, local Bcl-2 expression directly contributes to the modulation of local immune responses in allograft rejection, resulting in attenuated GCAD. In conclusion, our findings suggest that the modulation of Bcl-2 expression by pharmacologic up-regulation or gene transfer may be of clinical benefit in the short- and long-term function of cardiac allografts.