Guerrero-Beltrán Carlos Enrique, Bernal-Ramírez Judith, Lozano Omar, Oropeza-Almazán Yuriana, Castillo Elena Cristina, Garza Jesús Roberto, García Noemí, Vela Jorge, García-García Alejandra, Ortega Eduardo, Torre-Amione Guillermo, Ornelas-Soto Nancy, García-Rivas Gerardo
Cátedra de Cardiología y Medicina Vascular, Escuela Nacional de Medicina, Tecnológico de Monterrey, Monterrey, México.
Centro de Investigación Biomédica, Hospital Zambrano-Hellion, Tecnológico de Monterrey, San Pedro Garza-García, México.
Am J Physiol Heart Circ Physiol. 2017 Apr 1;312(4):H645-H661. doi: 10.1152/ajpheart.00564.2016. Epub 2017 Jan 27.
Recent evidence has shown that nanoparticles that have been used to improve or create new functional properties for common products may pose potential risks to human health. Silicon dioxide (SiO) has emerged as a promising therapy vector for the heart. However, its potential toxicity and mechanisms of damage remain poorly understood. This study provides the first exploration of SiO-induced toxicity in cultured cardiomyocytes exposed to 7- or 670-nm SiO particles. We evaluated the mechanism of cell death in isolated adult cardiomyocytes exposed to 24-h incubation. The SiO cell membrane association and internalization were analyzed. SiO showed a dose-dependent cytotoxic effect with a half-maximal inhibitory concentration for the 7 nm (99.5 ± 12.4 µg/ml) and 670 nm (>1,500 µg/ml) particles, which indicates size-dependent toxicity. We evaluated cardiomyocyte shortening and intracellular Ca handling, which showed impaired contractility and intracellular Ca transient amplitude during β-adrenergic stimulation in SiO treatment. The time to 50% Ca decay increased 39%, and the Ca spark frequency and amplitude decreased by 35 and 21%, respectively, which suggest a reduction in sarcoplasmic reticulum Ca-ATPase (SERCA) activity. Moreover, SiO treatment depolarized the mitochondrial membrane potential and decreased ATP production by 55%. Notable glutathione depletion and HO generation were also observed. These data indicate that SiO increases oxidative stress, which leads to mitochondrial dysfunction and low energy status; these underlie reduced SERCA activity, shortened Ca release, and reduced cell shortening. This mechanism of SiO cardiotoxicity potentially plays an important role in the pathophysiology mechanism of heart failure, arrhythmias, and sudden death. Silica particles are used as novel nanotechnology-based vehicles for diagnostics and therapeutics for the heart. However, their potential hazardous effects remain unknown. Here, the cardiotoxicity of silica nanoparticles in rat myocytes has been described for the first time, showing an impairment of mitochondrial function that interfered directly with Ca handling.
最近的证据表明，用于改善普通产品或赋予其新功能特性的纳米颗粒可能对人类健康构成潜在风险。二氧化硅（SiO）已成为一种有前景的心脏治疗载体。然而，其潜在毒性和损伤机制仍知之甚少。本研究首次探讨了暴露于7纳米或670纳米SiO颗粒的培养心肌细胞中SiO诱导的毒性。我们评估了分离的成年心肌细胞在24小时孵育后细胞死亡的机制。分析了SiO与细胞膜的结合及内化情况。SiO对7纳米（99.5±12.4微克/毫升）和670纳米（>1500微克/毫升）颗粒显示出剂量依赖性细胞毒性作用，这表明毒性具有尺寸依赖性。我们评估了心肌细胞缩短和细胞内钙处理情况，结果显示在SiO处理的β-肾上腺素能刺激过程中，收缩性受损，细胞内钙瞬变幅度降低。钙衰减至50%的时间增加了39%，钙火花频率和幅度分别降低了35%和21%，这表明肌浆网钙ATP酶（SERCA）活性降低。此外，SiO处理使线粒体膜电位去极化，并使ATP生成减少了55%。还观察到明显的谷胱甘肽耗竭和HO生成。这些数据表明，SiO增加了氧化应激，导致线粒体功能障碍和能量状态低下；这些是SERCA活性降低、钙释放缩短和细胞缩短的基础。这种SiO心脏毒性机制可能在心力衰竭、心律失常和猝死的病理生理机制中起重要作用。二氧化硅颗粒被用作基于纳米技术的心脏诊断和治疗新型载体。然而，它们的潜在有害影响仍然未知。在此，首次描述了二氧化硅纳米颗粒对大鼠心肌细胞的心脏毒性，显示出线粒体功能受损，直接干扰了钙处理。
