Involvement of polyamines in apoptosis of cardiac myoblasts in a model of simulated ischemia
Involvement of polyamines in apoptosis of cardiac myoblasts in a model of simulated ischemia
复制标题
DOI：
10.1016/j.yjmcc.2006.03.002
复制
发表时间：
2006-06-01
影响因子：
5
通讯作者：
Caldarera, Claudio M.
中科院分区：
文献类型：
--
作者：
Tantini, Benedetta;Fiumana, Emanuela;Caldarera, Claudio M.
心肌细胞的凋亡细胞死亡与多种心血管疾病有关，包括缺血、肥大和心力衰竭。多胺腐胺、亚精胺和精胺是细胞生长和分裂所必需的聚阳离子。然而，越来越多的证据表明多胺、细胞生长和细胞死亡可以紧密相连。在本文中，我们在模拟缺血模型中研究了多胺在 H9c2 心肌细胞凋亡中的作用。 H9c2 细胞暴露于模拟缺血条件下，包括缺氧和血清剥夺，从而诱导细胞凋亡。鸟氨酸脱羧酶是合成腐胺的多胺生物合成的限速酶，其活性在缺血细胞中被快速且短暂地诱导，在 3 It 后达到最大值，并导致多胺水平升高。 α-二氟甲基鸟氨酸 (DFMO) 对鸟氨酸脱羧酶的药理学抑制会消耗 H9c2 心肌细胞中的多胺，并保护细胞免受缺血诱导的细胞凋亡。 DFMO 抑制模拟缺血后的多种细胞凋亡分子事件，例如线粒体释放细胞色素 c、半胱天冬酶激活、Bcl-xL 下调和 DNA 片段化。当向细胞提供外源性腐胺时，DFMO 的保护作用就会消失，这表明多胺合成在模拟缺血模型中细胞凋亡的发展中具有特定作用。在从心脏中过度表达鸟氨酸脱羧酶的转基因小鼠获得的心肌细胞中，相对于来自对照小鼠的心肌细胞，诱导细胞凋亡后半胱天冬酶活化显着增加，证实了多胺的促细胞凋亡作用。首次提出多胺参与缺血性心肌细胞凋亡以及 DFMO 治疗有益效果的证据。总之，这一发现可能为保护缺血引起的心肌细胞损伤提供新的药理学方法。 (c) 2006 Elsevier Inc. 保留所有权利。
Apoptotic cell death of cardiomyocytes is involved in several cardiovascular diseases including ischemia, hypertrophy, and heart failure. The polyamines putrescine, spermidine, and spermine are polycations absolutely required for cell growth and division. However, increasing evidence indicates that polyamines, cell growth, and cell death can be tightly connected. In this paper, we have studied the involvement of polyamines in apoptosis of H9c2 cardiomyoblasts in a model of simulated ischemia. H9c2 cells were exposed to a condition of simulated ischemia, consisting of hypoxia plus serum deprivation, that induces apoptosis. The activity of ornithine decarboxylase, the rate limiting enzyme of polyamine biosynthesis that synthesizes putrescine, is rapidly and transiently induced in ischemic cells, reaching a maximum after 3 It, and leading to increased polyamine levels. Pharmacological inhibition of ornithine decarboxylase by alpha-difluoromethylomithine (DFMO) depletes H9c2 cardiomyoblasts of polyamines and protects the cells against ischemia-induced apoptosis. DFMO inhibits several of the molecular events of apoptosis that follow simulated ischemia, such as the release of cytochrome c from mitochondria, caspase activation, downregulation of Bcl-xL, and DNA fragmentation. The protective effect of DFMO is lost when exogenous putrescine is provided to the cells, indicating a specific role of polyamine synthesis in the development of apoptosis in this model of simulated ischemia. In cardiomyocytes obtained from transgenic mice overexpressing ornithine decarboxylase in the heart, caspase activation is dramatically increased following induction of apoptosis, with respect to cardiomyocytes from control mice, confirming a proapoptotic effect of polyamines. It is presented for the first time evidence of the involvement of polyamines in apoptosis of ischemic cardiac cells and the beneficial effect of DFMO treatment. In conclusion, this finding may suggest novel pharmacological approaches for the protection of cardiomyocytes injury caused by ischemia. (c) 2006 Elsevier Inc. All rights reserved.