Antiretroviral therapy have significantly improved the treatment of viral infections and reduced the associated mortality and morbidity rates. However, highly effective antiretroviral therapy (HAART) may lead to an increased risk of cardiovascular diseases, which could be related to endothelial toxicity. Here, seven antiviral drugs (remdesivir, PF-00835231, ritonavir, lopinavir, efavirenz, zidovudine and abacavir) were characterized against aortic (HAEC) and pulmonary (hLMVEC) endothelial cells, using high-content microscopy. The colourimetric study (MTS test) revealed similar toxicity profiles of all antiviral drugs tested in the concentration range of 1 nM-50 μM in aortic and pulmonary endothelial cells. Conversely, the drugs' effects on morphological parameters were more pronounced in HAECs as compared with hLMVECs. Based on the antiviral drugs' effects on the cytoplasmic and nuclei architecture (analyzed by multiple pre-defined parameters including SER texture and STAR morphology), the studied compounds were classified into five distinct morphological subgroups, each linked to a specific cellular response profile. In relation to morphological subgroup classification, antiviral drugs induced a loss of mitochondrial membrane potential, elevated ROS, changed lipid droplets/lysosomal content, decreased von Willebrand factor expression and micronuclei formation or dysregulated cellular autophagy. In conclusion, based on specific changes in endothelial cytoplasm, nuclei and subcellular morphology, the distinct endothelial response was identified for remdesivir, ritonavir, lopinavir, efavirenz, zidovudine and abacavir treatments. The effects detected in aortic endothelial cells were not detected in pulmonary endothelial cells. Taken together, high-content microscopy has proven to be a robust and informative method for endothelial drug profiling that may prove useful in predicting the organ-specific endothelial toxicity of various drugs.
Keyphrases
- endothelial cells
- antiretroviral therapy
- high glucose
- pulmonary hypertension
- hiv infected
- hiv infected patients
- oxidative stress
- aortic valve
- pulmonary artery
- drug induced
- vascular endothelial growth factor
- hiv aids
- human immunodeficiency virus
- hiv positive
- single cell
- high throughput
- cardiovascular disease
- single molecule
- cell death
- emergency department
- machine learning
- stem cells
- left ventricular
- aortic dissection
- risk factors
- risk assessment
- binding protein
- sars cov
- computed tomography
- clinical trial
- bone marrow
- optical coherence tomography
- randomized controlled trial
- cardiovascular events
- pulmonary arterial hypertension
- endoplasmic reticulum stress
- metabolic syndrome
- diabetic rats
- dna damage