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  3. Establishment of an in vitro safety assessment model for lipid-lowering drugs using same-origin human pluripotent stem cell-derived cardiomyocytes and endothelial cells

Establishment of an in vitro safety assessment model for lipid-lowering drugs using same-origin human pluripotent stem cell-derived cardiomyocytes and endothelial cells

  • Acta Pharmacol Sin. 2022 Jan;43(1):240-250. doi: 10.1038/s41401-021-00621-8.
Xuan Ni 1,  Zhuang-Zhuang Yang 1,  Ling-Qun Ye 1,  Xing-Long Han 1,  Dan-Dan Zhao 1,  Feng-Yue Ding 1,  Nan Ding 1,  Hong-Chun Wu 1,  Miao Yu 1,  Guang-Yin Xu 2,  Zhen-Ao Zhao 3,  Wei Lei 1,  Shi-Jun Hu 4
Affiliations

Affiliations

  • 1 Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, 215000, China.
  • 2 Institute of Neuroscience, Soochow University, Suzhou, 215123, China.
  • 3 Institute of Microcirculation, Department of Pathophysiology of Basic Medical College, Hebei North University, Zhangjiakou, 075000, China.
  • 4 Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, 215000, China. shijunhu@suda.edu.cn.
PMID: 33686244 DOI: 10.1038/s41401-021-00621-8
Abstract

Cardiovascular safety assessment is vital for drug development, yet human cardiovascular cell models are lacking. In vitro mass-generated human pluripotent stem cell (hPSC)-derived cardiovascular cells are a suitable cell model for preclinical cardiovascular safety evaluations. In this study, we established a preclinical toxicology model using same-origin hPSC-differentiated cardiomyocytes (hPSC-CMs) and endothelial cells (hPSC-ECs). For validation of this cell model, alirocumab, a human antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), was selected as an emerging safe lipid-lowering drug; atorvastatin, a common statin (the most effective type of lipid-lowering drug), was used as a drug with reported side effects at high concentrations, while doxorubicin was chosen as a positive cardiotoxic drug. The cytotoxicity of these drugs was assessed using CCK8, ATP, and Lactate Dehydrogenase release assays at 24, 48, and 72 h. The influences of these drugs on cardiomyocyte electrophysiology were detected using the patch-clamp technique, while their effects on endothelial function were determined by tube formation and Dil-acetylated low-density lipoprotein (Dil-Ac-LDL) uptake assays. We showed that alirocumab did not affect the cell viability or cardiomyocyte electrophysiology in agreement with the clinical results. Atorvastatin (5-50 μM) dose-dependently decreased cardiovascular cell viability over time, and at a high concentration (50 μM, ~100 times the normal peak serum concentration in clinic), it affected the action potentials of hPSC-CMs and damaged tube formation and Dil-Ac-LDL uptake of hPSC-ECs. The results demonstrate that the established same-origin hPSC-derived cardiovascular cell model can be used to evaluate lipid-lowering drug safety in cardiovascular cells and allow highly accurate preclinical assessment of potential drugs.

Keywords

alirocumab; atorvastatin; cardiomyocytes; doxorubicin; drug safety; endothelial cells; lipid-lowering drugs; pluripotent stem cells.

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