Lovastatin-induced cardiac toxicity involves both oncotic and apoptotic cell death with the apoptotic component blunted by both caspase-2 and caspase-3 inhibitors.
Lovastatin-induced cardiac toxicity involves both oncotic and apoptotic cell death with the apoptotic component blunted by both caspase-2 and caspase-3 inhibitors.
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DOI：
10.1016/j.taap.2003.08.009
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发表时间：
2003-12
影响因子：
3.8
通讯作者：
S. Rabkin;J. Kong
中科院分区：
文献类型：
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作者：
S. Rabkin;J. Kong
本研究的目的是通过验证洛伐他汀诱导心肌细胞凋亡和/或肿瘤性细胞死亡的假说，进一步验证细胞死亡是通过阻断甲羟戊酸途径以及通过激活caspase-2和caspase-3来诱导凋亡的假说，来评价HMG-CoA还原酶抑制剂的心脏毒性。从鸡胚胎心脏中分离培养出心肌细胞。洛伐他汀可通过三种独立的技术证实洛伐他汀诱导的细胞凋亡：(1)碘化丙啶(PI)对低DNA含量的FACS分析；(2)细胞凋亡的显微镜观察；(3)PI和二醋酸荧光素染色细胞的FACS分析。洛伐他汀使细胞凋亡率呈浓度依赖性增加，与对照组相比，100μ洛伐他汀的凋亡率增加了4倍以上。洛伐他汀也会导致肿瘤细胞死亡，因为与对照组相比，肿瘤细胞死亡的数量增加了2.5倍。洛伐他汀诱导的细胞凋亡部分是通过甲氧戊酸途径进行的。Caspase-2抑制剂z-VDVAD-fmk和caspase-3抑制剂Ac-DEVD-CHO可降低洛伐他汀诱导的心肌细胞凋亡的程度。相反，洛伐他汀诱导的肿胀不仅对这些caspase-2或-3抑制剂不敏感，而且是通过甲氧戊酸非依赖的作用机制发生的。总之，洛伐他汀诱导的心脏毒性是复杂的，代表了两种不同的细胞死亡模式的总和，部分通过甲氧戊酸途径进行操作，凋亡成分受到caspase启动子caspase-2和效应子caspase-3抑制剂的修饰。
The objective of this study was to evaluate the cardiac toxicity of the HMG–CoA reductase inhibitors by testing the hypothesis that lovastatin induces apoptotic and/or oncotic cell death in the myocyte element of the heart and further that cell death is mediated through interruption of the mevalonate pathway and that apoptosis is induced through activation of caspase-2 and caspase-3. Cardiomyocytes were cultured from embryonic chick heart. Lovastatin-induced apoptosis in these cells was demonstrated by three independent techniques, namely (1) FACS analysis of low DNA content by propidium iodide (PI); (2) microscopic assessment for cellular changes of apoptosis; and (3) FACS analysis of cells stained with PI and fluoroscein diacetate. Lovastatin produced a concentration-dependent increase in apoptotic cell death and 100 μM lovastatin showed over a 4-fold increase in apoptosis compared to control. Lovastatin also induced oncotic cell death, as there was a 2.5-fold increase in the amount of oncotic cell death compared to control. Lovastatin-induced apoptosis operated, in part, through the mevalonate pathway. The caspase-2 inhibitor z-VDVAD-fmk and the caspase-3 inhibitor Ac-DEVD-CHO reduced the extent of lovastatin-induced cardiac apoptosis. In contrast, lovastatin-induced oncosis was not only insensitive to these caspase-2 or -3 inhibitors but occurred through a mevalonate-independent mechanism of action. In summary, lovastatin-induced cardiotoxicty is complex and represents the sum of two distinct modes of cell death operating in part through the mevalonate pathway with the apoptotic component subject to modification by inhibitors of the initiator caspase, caspase-2, as well as the effector caspase, caspase-3.