Nuclear Factor- (cid:1) B–Mediated Cell Survival Involves Transcriptional Silencing of the Mitochondrial Death Gene BNIP3 in Ventricular Myocytes
Nuclear Factor- (cid:1) B–Mediated Cell Survival Involves Transcriptional Silencing of the Mitochondrial Death Gene BNIP3 in Ventricular Myocytes
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背景-转录因子核因子- (cid:1) B （NF- (cid:1) B）在心室肌细胞中的存活作用已有报道；然而，其基本机制尚未定义。在本报告中，我们提供了新的机制证据，证明NF- (cid:1) B赋予的生存信号影响缺氧诱导的死亡因子BNIP3。方法与结果- IKK （cid:2）激活心室肌细胞NF- (cid:1) B信号通路可抑制BNIP3引起的线粒体通透性过渡孔（PTP）开放和细胞死亡。IKK （cid:2）或p65 NF- (cid:1) B的表达抑制了基础和缺氧诱导的BNIP3基因活性。对bbnip3启动子的缺失分析表明，NF- (cid:1) B元件对抑制bbnip3基础和诱导基因活性至关重要。来源于p65 (cid:1) / (cid:1)缺陷小鼠或NF- (cid:1) B非磷酸化I (cid:1) B信号传导缺陷的心室肌细胞的细胞表现出BNIP3基因基础表达增加、线粒体PTP增加和细胞死亡。NF- (cid:1) b缺陷肌细胞中BNIP3基因的遗传或功能性消融可使其免于线粒体缺陷和细胞死亡。结论-数据提供了新的令人信服的证据，NF- (cid:1) B通过转录沉默死亡基因BNIP3的机制抑制线粒体缺陷和心室肌细胞死亡。总的来说，我们的数据为NF- (cid:1) B抑制细胞死亡的模式提供了新的机制见解，并确定BNIP3是NF- (cid:1) B调节心室肌细胞表达的关键转录靶点。(循环。2005; 112:3777 - 3785)。我们早期的工作发现BNIP3是缺氧损伤期间细胞死亡过程中的一个核心因素。我们证明，在正常氧张力下，BNIP3不会对细胞的活力构成威胁，因为它被细胞因子核因子- (cid:1) B （NF- (cid:1) B）“关闭”。NF- (cid:1) B的生物作用类似于汽车的刹车，防止汽车移动。我们发现在缺氧时NF- (cid:1) B失活，释放“刹车”并“打开”BNIP3。这导致BNIP3水平升高和心脏细胞死亡。此外，我们发现“模仿”NF- (cid:1) B的制动作用的遗传干预可以抑制BNIP3基因的激活和缺氧时心室肌细胞的细胞死亡。这项研究的临床重要性为设计新的治疗方法提供了希望，这些治疗方法专门针对细胞死亡途径的成分，作为预防梗死后患者细胞过度损失和改善心室功能的一种手段。
Background —A survival role for the transcription factor nuclear factor- (cid:1) B (NF- (cid:1) B) in ventricular myocytes has been reported; however, the underlying mechanism is undefined. In this report we provide new mechanistic evidence that survival signals conferred by NF- (cid:1) B impinge on the hypoxia-inducible death factor BNIP3. Methods and Results —Activation of the NF- (cid:1) B signaling pathway by IKK (cid:2) in ventricular myocytes suppressed mitochondrial permeability transition pore (PTP) opening and cell death provoked by BNIP3. Expression of IKK (cid:2) or p65 NF- (cid:1) B suppressed basal and hypoxia-inducible BNIP3 gene activity. Deletion analysis of the BNIP3 promoter revealed the NF- (cid:1) B elements to be crucial for inhibiting basal and inducible BNIP3 gene activity. Cells derived from p65 (cid:1) / (cid:1) -deficient mice or ventricular myocytes rendered defective for NF- (cid:1) B signaling with a nonphosphorylative I (cid:1) B exhibited increased basal BNIP3 gene expression, mitochondrial PTP, and cell death. Genetic or functional ablation of the BNIP3 gene in NF- (cid:1) B–defective myocytes rescued them from mitochondrial defects and cell death. Conclusions —The data provide new compelling evidence that NF- (cid:1) B suppresses mitochondrial defects and cell death of ventricular myocytes through a mechanism that transcriptionally silences the death gene BNIP3. Collectively, our data provide new mechanistic insight into the mode by which NF- (cid:1) B suppresses cell death and identify BNIP3 as a key transcriptional target for NF- (cid:1) B–regulated expression in ventricular myocytes. ( Circulation . 2005;112:3777-3785.) Our earlier work identified BNIP3 to be a central factor in the cell death process during hypoxic injury. We demonstrate that under normal oxygen tension, BNIP3 poses no threat to the viability of the cell because it is “switched off” by the cellular factor nuclear factor- (cid:1) B (NF- (cid:1) B). The biological actions of NF- (cid:1) B work in a way analogous to the brakes of a car, which prevent the car from moving. We show that during hypoxia NF- (cid:1) B is inactivated, releasing the “brakes” and “switching on” BNIP3. This results in elevated BNIP3 levels and cell death of heart cells. Furthermore, we show that genetic interventions that “mimic” the braking actions of NF- (cid:1) B suppress BNIP3 gene activation and cell death of ventricular myocytes during hypoxia. The clinical importance of this study holds promise for the design of new therapies that specifically target components of the cell death pathway as a means to prevent inordinate cell loss and improve ventricular function in patients after infarction.