Pretreatment with Statin Attenuates the Cardiotoxicity of Doxorubicin in Mice
Pretreatment with Statin Attenuates the Cardiotoxicity of Doxorubicin in Mice
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DOI：
10.1158/0008-5472.can-08-3076
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发表时间：
2009-01-15
期刊：
影响因子：
11.2
通讯作者：
Tschoepe, Carsten
中科院分区：
文献类型：
--
作者：
Riad, Alexander;Bien, Sandra;Tschoepe, Carsten
心脏毒性，这可能是由于强烈的心脏氧化应激和炎症，是使用阿霉素的抗癌治疗的主要限制因素。由于他汀类药物可能发挥有益的多效性心血管效应，除其他外，抗炎和抗氧化预处理，我们研究是否氟伐他汀预处理可以减轻阿霉素诱导的心脏毒性。单次注射阿霉素（20 mg/kg; i. p.）后5天，在氟伐他汀处理的（DoxStatin; 100 mg/kg/天，p.o.）和盐水处理的（多柔比星）小鼠（每组n = 8）。未处理的小鼠作为对照（安慰剂;每组n = 8）。心功能测定后，用分子生物学和免疫组织化学方法对IN组织进行分析。与安慰剂相比，注射导致IN功能显著受损（LV压力，-29%; dp/dtmax，-45%;心输出量，-68%; P < 0.05）。心肌脂质过氧化活性、硝基酪氨酸、肿瘤坏死因子α和Bax蛋白表达显著增加（P < 0.05），心肌氧化应激、炎症反应和凋亡机制明显增强。相比之下，当与未处理的阿霉素小鼠相比时，DoxStatin小鼠显示出改善的LV功能（LV压力，+24%; dp/dtmax，+87%;心输出量，+87%; P < 0.05）。这与心脏硝基酪氨酸表达减少、线粒体定位的抗氧化SOD 2表达增强、线粒体凋亡途径减弱和心脏炎症反应减少有关。他汀类药物预处理通过抗氧化和抗炎作用减轻阿霉素诱导的心脏毒性。[Cancer Iles 2009;69（2）：695-9]
Cardiotoxicity, which may result from intense cardiac oxidative stress and inflammation, is the main limiting factor of the anticancer therapy using doxorubicin. Because statins might exert beneficial pleiotropic cardiovascular effects, among other things, by anti-inflammatory and antioxidative pretreatnisms, we investigated whether or not fluvastatin pretreatment can attenuate doxorubicin-induced cardiotoxicity. Five days after a single injection of doxorubicin (20 mg/kg; i.p.), left ventricular (LV) function was measured in fluvastatin-treated (DoxStatin; 100 mg/kg/day, p.o.) and saline-treated (doxorubicin) mice (n = 8 per group) by a micro conductance catheter. Untreated mice served as controls (placebo; n = 8 per group). After measurement of cardiac function, IN tissues were analyzed by molecular biological and immunohistologic methods. Injection resulted in significantly impaired IN function (LV pressure, -29%; dp/dtmax, -45%; cardiac output, -68%,; P < 0.05) when compared with placebo. This was associated with a significant increase in cardiac oxidative stress, inflammation and apoptotic mechanisms, as indicated by significant increased cardiac lipid peroxidation activity, protein expression of nitrotyrosine, tumor necrosis factor a and Bax (P < 0.05). In contrast, DoxStatin mice showed improved LV function (LV pressure, +24%; dp/dtmax, +87%; cardiac output, +87%; P < 0.05) when compared with untreated doxorubicin mice. This was associated with reduced cardiac expression of nitrotyrosine, enhanced expression of the mitochondrial located antioxidative SOD 2, attenuated mitochondrial apoptotic pathways, and reduced cardiac inflammatory response. Statin pretreatment attenuates doxorubicin-induced cardiotoxicity via antioxidative and anti-inflammatory effects. [Cancer Iles 2009;69(2):695-9]