Hydroxymethylglutaryl-coenzyme A reductase inhibitors induce apoptosis in human cardiac myocytes in vitro
Hydroxymethylglutaryl-coenzyme A reductase inhibitors induce apoptosis in human cardiac myocytes in vitro
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DOI：
10.1016/j.bcp.2006.01.016
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发表时间：
2006-04-28
影响因子：
5.8
通讯作者：
Wojta, J
中科院分区：
文献类型：
--
作者：
Demyanets, S;Kaun, C;Wojta, J
最近的研究发现，羟甲基戊二酰辅酶A （HMG-CoA）还原酶抑制剂或他汀类药物（一种治疗高胆固醇血症的药物）与心脏组织重塑有关。他汀类药物在不同的细胞培养系统中诱导细胞凋亡，包括大鼠新生心肌细胞。我们在体外研究了不同的他汀类药物对人成人心肌细胞中被认为参与细胞凋亡调节的蛋白表达的可能影响，如Mcl-1（一种细胞凋亡抑制剂）、Bax（一种细胞凋亡诱导剂）以及细胞质组蛋白相关dna片段。不同浓度的他汀类药物（浓度为0.01 ~ 5 μ M）作用于成人心肌细胞（HACM）长达96小时。5 μ M浓度的亲脂性他汀辛伐他汀可下调Mcl-1 mRNA 49%，而亲水的普伐他汀则没有作用。两种他汀类药物均未影响Bax mRNA水平。辛伐他汀而非普伐他汀降低Mcl-1蛋白表达，而Western blotting检测ham中未检测到Bax蛋白。辛伐他汀、阿托伐他汀和氟伐他汀诱导组蛋白相关dna片段增加高达7倍，而普伐他汀没有。辛伐他汀呈剂量依赖性上调组蛋白相关dna片段，甲羟戊酸和焦磷酸香叶基香叶基将这种作用逆转至控制水平。我们的研究结果表明，亲脂性他汀类药物可以诱导体外成人心肌细胞的促凋亡状态。我们推测，与动物模型的发现类似，他汀类药物可能通过调节细胞存活和凋亡之间的平衡，参与人类心脏肥厚和重塑的衰减。(c) 2006爱思唯尔公司版权所有。
Recent findings have implicated hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins, an established class of drugs for the treatment of hypercholesterolemia, in tissue remodeling in the heart. Statins induce apoptosis in different cell culture systems including rat neonatal cardiomyocytes. We investigated possible effects of different statins in vitro in human adult cardiac myocytes on the expression of proteins thought to be involved in the regulation of apoptosis such as Mcl-1, an inhibitor of apoptosis, Bax, an inducer of apoptosis, as well as on cytoplasmic histone-associated-DNA-fragments. Human adult cardiac myocytes (HACM) were treated with different statins at concentrations from 0.01 to 5 mu M for up to 96 h. Whereas the lipophilic statin simvastatin at a concentration of 5 mu M downregulated Mcl-1 mRNA by 49%, the hydrophilic pravastatin had no effect. Bax mRNA levels were not affected by neither of the statins. Simvastatin but not pravastatin reduced Mcl-1 protein expression whereas Bax protein was not detectable in HACM as determined by Western blotting. Simvastatin, atorvastatin and fluvastatin induced an up to seven-fold increase in histone-associated-DNA-fragments whereas pravastatin did not. Simvastatin up regulated histone-associated-DNA-fragments dose - dependently, and mevalonate and geranylgeranyl pyrophosphate reversed this effect to control levels. Our results show that lipophilic statins can induce a pro-apoptotic state in human adult cardiac myocytes in vitro. We speculate that, similar to findings in animal models, statins might be involved in the attenuation of cardiac hypertrophy and remodeling in humans by modulating the balance between cell survival and apoptosis. (c) 2006 Elsevier Inc. All rights reserved.