Silica nanoparticles (nanoSiO2) are promising systems that can deliver biologically active compounds to tissues such as the heart in a controllable manner. However, cardiac toxicity induced by nanoSiO2 has been recently related to abnormal calcium handling and energetic failure in cardiomyocytes. Moreover, the precise mechanisms underlying this energetic debacle remain unclear. In order to elucidate these mechanisms, this article explores the ex vivo heart function and mitochondria after exposure to nanoSiO2. The cumulative administration of nanoSiO2 reduced the mechanical performance index of the rat heart with a half-maximal inhibitory concentration (IC50) of 93 μg/mL, affecting the relaxation rate. In isolated mitochondria nanoSiO2 was found to be internalized, inhibiting oxidative phosphorylation and significantly reducing the mitochondrial membrane potential (ΔΨm). The mitochondrial permeability transition pore (mPTP) was also induced with an increasing dose of nanoSiO2 and partially recovered with, a potent blocker of the mPTP, Cyclosporine A (CsA). The activity of aconitase and thiol oxidation, in the adenine nucleotide translocase, were found to be reduced due to nanoSiO2 exposure, suggesting that nanoSiO2 induces the mPTP via thiol modification and ROS generation. In cardiac cells exposed to nanoSiO2, enhanced viability and reduction of H2O2 were observed after application of a specific mitochondrial antioxidant, MitoTEMPO. Concomitantly, CsA treatment in adult rat cardiac cells reduced the nanoSiO2-triggered cell death and recovered ATP production (from 32.4 to 65.4%). Additionally, we performed evaluation of the mitochondrial effect of nanoSiO2 in human cardiomyocytes. We observed a 40% inhibition of maximal oxygen consumption rate in mitochondria at 500 μg/mL. Under this condition we identified a remarkable diminution in the spare respiratory capacity. This data indicates that a reduction in the amount of extra ATP that can be produced by mitochondria during a sudden increase in energy demand. In human cardiomyocytes, increased LDH release and necrosis were found at increased doses of nanoSiO2, reaching 85 and 48%, respectively. Such deleterious effects were partially prevented by the application of CsA. Therefore, exposure to nanoSiO2 affects cardiac function via mitochondrial dysfunction through the opening of the mPTP. The aforementioned effects can be partially avoided reducing ROS or retarding the opening of the mPTP. These novel strategies which resulted in cardioprotection could be considered as potential therapies to decrease the side effects of nanoSiO2 exposure.

中文翻译：

---

非晶态SiO2纳米颗粒通过大鼠心脏和人心肌细胞中线粒体通透性过渡孔的开放来促进心脏功能障碍。

二氧化硅纳米粒子（nanoSiO2）是有前途的系统，可以将生物活性化合物以可控方式传递到组织（例如心脏）。然而，近来由nanoSiO 2诱导的心脏毒性与心肌细胞中钙的异常处理和能量衰竭有关。此外，这种高能崩溃的确切机制仍不清楚。为了阐明这些机制，本文探讨了暴露于nanoSiO2后的离体心脏功能和线粒体。纳米二氧化硅的累积给药降低了大鼠心脏的机械性能指数，最大抑制浓度（IC50）达到一半，为93μg/ mL，影响了舒张率。在孤立的线粒体中，发现SiO2被内在化，抑制氧化磷酸化并显着降低线粒体膜电位（ΔΨm）。线粒体通透性过渡孔（mPTP）也可以通过增加剂量的nanoSiO2来诱导，并通过mPTP的强效阻断剂环孢菌素A（CsA）进行部分回收。发现腺嘌呤核苷酸转位酶中乌头酸酶和硫醇氧化的活性由于暴露于nanoSiO2而降低，这表明nanoSiO2通过巯基修饰和ROS的产生诱导了mPTP。在应用纳米线粒抗氧化剂MitoTEMPO后，在暴露于nanoSiO2的心肌细胞中，观察到了增强的活力和H2O2的减少。伴随地，成年大鼠心脏细胞中的CsA处理降低了nanoSiO2触发的细胞死亡并恢复了ATP的产生（从32.4％降至65.4％）。另外，我们对人心肌细胞中nanoSiO2的线粒体作用进行了评估。我们观察到在500μg/ mL的线粒体中最大耗氧率受到40％的抑制。在这种情况下，我们发现备用呼吸能力显着下降。该数据表明，在能量需求突然增加的过程中，线粒体可能产生的额外ATP数量减少。在人类心肌细胞中，当纳米SiO2剂量增加时，发现LDH释放增加和坏死，分别达到85％和48％。通过使用CsA可以部分防止这种有害作用。因此，暴露于nanoSiO2会通过打开mPTP通过线粒体功能障碍影响心脏功能。可以部分避免上述效果，从而减少ROS或延迟mPTP的开放。