Pierzchalski P, Reiss K, Cheng W, Cirielli C, Kajstura J, Nitahara J A, Rizk M, Capogrossi M C, Anversa P
Department of Medicine, New York Medical College, Valhalla 10595, USA.
Exp Cell Res. 1997 Jul 10;234(1):57-65. doi: 10.1006/excr.1997.3604.
The mechanism by which p53 activates apoptosis in various cell systems is unknown. In the absence of an external death stimulus, p53 and p53-dependent genes, bcl-2 and bax, cannot trigger apoptosis. However, p53 may enhance not only transcription of bax and repress bcl-2, but also may upregulate the local renin-angiotensin system, inducing the formation and secretion of angiotensin II from the cells. To test this hypothesis, adult rat ventricular myocytes were infected with AdCMV.p53, which resulted in downregulation of Bcl-2, upregulation of Bax, and death of 34% of the cells. Gel retardation assays demonstrated p53 binding in the promoters of angiotensinogen and angiotensin II AT1 receptor subtype. Angiotensinogen and AT1 mRNAs increased in AdCMV.p53 cells and this phenomenon was associated with a 14-fold increase in the secretion of angiotensin II. The AT1 receptor blocker losartan and angiotensin II antibody prevented p53-induced apoptosis. Thus, p53 enhances the myocyte renin-angiotensin-system and decreases the Bcl-2/Bax ratio in the cells, triggering apoptosis. The identification of this new pathway in p53-mediated apoptosis may be critical in the alterations of myocardial function in the pathologic heart.
p53在各种细胞系统中激活细胞凋亡的机制尚不清楚。在没有外部死亡刺激的情况下，p53以及p53依赖性基因bcl-2和bax无法触发细胞凋亡。然而，p53不仅可能增强bax的转录并抑制bcl-2，还可能上调局部肾素-血管紧张素系统，诱导细胞中血管紧张素II的形成和分泌。为了验证这一假设，用AdCMV.p53感染成年大鼠心室肌细胞，结果导致Bcl-2下调、Bax上调，34%的细胞死亡。凝胶阻滞分析表明p53结合在血管紧张素原和血管紧张素II AT1受体亚型的启动子上。AdCMV.p53细胞中血管紧张素原和AT1 mRNA增加，这一现象与血管紧张素II分泌增加14倍有关。AT1受体阻滞剂氯沙坦和血管紧张素II抗体可预防p53诱导的细胞凋亡。因此，p53增强心肌细胞肾素-血管紧张素系统并降低细胞中的Bcl-2/Bax比值，触发细胞凋亡。在p53介导的细胞凋亡中鉴定出这一新途径可能对病理性心脏中心肌功能的改变至关重要。
