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Zinc Oxide Nanoparticles Induce Mitochondrial Biogenesis Impairment and Cardiac Dysfunction in Human iPSC-Derived Cardiomyocytes.
Int J Nanomedicine. 2020; 15:2669-2683.IJ

Abstract

Background

Zinc oxide nanoparticles (ZnO NPs) are one of the most widely used nanomaterials in a variety of fields such as industrial, pharmaceutical, and household applications. Increasing evidence suggests that ZnO NPs could elicit unignorable harmful effect to the cardiovascular system, but the potential deleterious effects to human cardiomyocytes remain to be elucidated. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been increasingly used as a promising in vitro model of cardiomyocyte in various fields such as drug cardiac safety evaluation. Herein, the present study was designed to elucidate the cardiac adverse effects of ZnO NPs and explore the possible underlying mechanism using hiPSC-CMs.

Methods

ZnO NPs were characterized by transmission electron microscopy and dynamic light scattering. The cytotoxicity induced by ZnO NPs in hiPSC-CMs was evaluated by determination of cell viability and lactate dehydrogenase release. Cellular reactive oxygen species (ROS) and mitochondrial membrane potential were measured by high-content analysis (HCA). Mitochondrial biogenesis was assayed by detection of mtDNA copy number and PGC-1α pathway. Moreover, microelectrode array techniques were used to investigate cardiac electrophysiological alterations.

Results

We demonstrated that ZnO NPs concentration- and time-dependently elicited cytotoxicity in hiPSC-CMs. The results from HCA revealed that ZnO NPs exposure at low-cytotoxic concentrations significantly promoted ROS generation and induced mitochondrial dysfunction. We further demonstrated that ZnO NPs could impair mitochondrial biogenesis and inhibit PGC-1α pathway. In addition, ZnO NPs at insignificantly cytotoxic concentrations were found to trigger cardiac electrophysiological alterations as evidenced by decreases of beat rate and spike amplitude.

Conclusion

Our findings unveiled the potential harmful effects of ZnO NPs to human cardiomyocytes that involve mitochondrial biogenesis and the PGC-1α pathway that could affect cardiac electrophysiological function.

Authors+Show Affiliations

Graduate School, Academy of Military Medical Sciences, Beijing, People's Republic of China. Department of Operational Medical Protection, PLA Center for Disease Control and Prevention, Beijing, People's Republic of China.Department of Operational Medical Protection, PLA Center for Disease Control and Prevention, Beijing, People's Republic of China.Department of Operational Medical Protection, PLA Center for Disease Control and Prevention, Beijing, People's Republic of China.Department of Operational Medical Protection, PLA Center for Disease Control and Prevention, Beijing, People's Republic of China.Department of Operational Medical Protection, PLA Center for Disease Control and Prevention, Beijing, People's Republic of China.Beijing Key Laboratory for Cardiovascular Precision Medicines, Anzhen Hospital, Capital Medical University, Beijing, People's Republic of China.Department of Operational Medical Protection, PLA Center for Disease Control and Prevention, Beijing, People's Republic of China.Graduate School, Academy of Military Medical Sciences, Beijing, People's Republic of China. Department of Operational Medical Protection, PLA Center for Disease Control and Prevention, Beijing, People's Republic of China.Graduate School, Academy of Military Medical Sciences, Beijing, People's Republic of China. Department of Operational Medical Protection, PLA Center for Disease Control and Prevention, Beijing, People's Republic of China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32368048

Citation

Li, Yujie, et al. "Zinc Oxide Nanoparticles Induce Mitochondrial Biogenesis Impairment and Cardiac Dysfunction in Human iPSC-Derived Cardiomyocytes." International Journal of Nanomedicine, vol. 15, 2020, pp. 2669-2683.
Li Y, Li F, Zhang L, et al. Zinc Oxide Nanoparticles Induce Mitochondrial Biogenesis Impairment and Cardiac Dysfunction in Human iPSC-Derived Cardiomyocytes. Int J Nanomedicine. 2020;15:2669-2683.
Li, Y., Li, F., Zhang, L., Zhang, C., Peng, H., Lan, F., Peng, S., Liu, C., & Guo, J. (2020). Zinc Oxide Nanoparticles Induce Mitochondrial Biogenesis Impairment and Cardiac Dysfunction in Human iPSC-Derived Cardiomyocytes. International Journal of Nanomedicine, 15, 2669-2683. https://doi.org/10.2147/IJN.S249912
Li Y, et al. Zinc Oxide Nanoparticles Induce Mitochondrial Biogenesis Impairment and Cardiac Dysfunction in Human iPSC-Derived Cardiomyocytes. Int J Nanomedicine. 2020;15:2669-2683. PubMed PMID: 32368048.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Zinc Oxide Nanoparticles Induce Mitochondrial Biogenesis Impairment and Cardiac Dysfunction in Human iPSC-Derived Cardiomyocytes. AU - Li,Yujie, AU - Li,Fengxiang, AU - Zhang,Lincong, AU - Zhang,Chi, AU - Peng,Hui, AU - Lan,Feng, AU - Peng,Shuangqing, AU - Liu,Chao, AU - Guo,Jiabin, Y1 - 2020/04/21/ PY - 2020/02/15/received PY - 2020/04/01/accepted PY - 2020/5/6/entrez PY - 2020/5/6/pubmed PY - 2020/7/3/medline KW - PGC-1α KW - Zinc oxide nanoparticles KW - ZnO NPs KW - cardiac dysfunction KW - hiPSC-CMs KW - human induced pluripotent stem cells-derived cardiomyocytes KW - mitochondrial biogenesis SP - 2669 EP - 2683 JF - International journal of nanomedicine JO - Int J Nanomedicine VL - 15 N2 - Background: Zinc oxide nanoparticles (ZnO NPs) are one of the most widely used nanomaterials in a variety of fields such as industrial, pharmaceutical, and household applications. Increasing evidence suggests that ZnO NPs could elicit unignorable harmful effect to the cardiovascular system, but the potential deleterious effects to human cardiomyocytes remain to be elucidated. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have been increasingly used as a promising in vitro model of cardiomyocyte in various fields such as drug cardiac safety evaluation. Herein, the present study was designed to elucidate the cardiac adverse effects of ZnO NPs and explore the possible underlying mechanism using hiPSC-CMs. Methods: ZnO NPs were characterized by transmission electron microscopy and dynamic light scattering. The cytotoxicity induced by ZnO NPs in hiPSC-CMs was evaluated by determination of cell viability and lactate dehydrogenase release. Cellular reactive oxygen species (ROS) and mitochondrial membrane potential were measured by high-content analysis (HCA). Mitochondrial biogenesis was assayed by detection of mtDNA copy number and PGC-1α pathway. Moreover, microelectrode array techniques were used to investigate cardiac electrophysiological alterations. Results: We demonstrated that ZnO NPs concentration- and time-dependently elicited cytotoxicity in hiPSC-CMs. The results from HCA revealed that ZnO NPs exposure at low-cytotoxic concentrations significantly promoted ROS generation and induced mitochondrial dysfunction. We further demonstrated that ZnO NPs could impair mitochondrial biogenesis and inhibit PGC-1α pathway. In addition, ZnO NPs at insignificantly cytotoxic concentrations were found to trigger cardiac electrophysiological alterations as evidenced by decreases of beat rate and spike amplitude. Conclusion: Our findings unveiled the potential harmful effects of ZnO NPs to human cardiomyocytes that involve mitochondrial biogenesis and the PGC-1α pathway that could affect cardiac electrophysiological function. SN - 1178-2013 UR - https://www.unboundmedicine.com/medline/citation/32368048/Zinc_Oxide_Nanoparticles_Induce_Mitochondrial_Biogenesis_Impairment_and_Cardiac_Dysfunction_in_Human_iPSC-Derived_Cardiomyocytes L2 - https://dx.doi.org/10.2147/IJN.S249912 DB - PRIME DP - Unbound Medicine ER -