Remdesivir Inhibits the Activation of Vascular Smooth Muscle Cells via the Induction of Heme Oxygenase-1

Coronavirus disease 2019 (COVID-19) causes major cardiovascular complications that contributes to the high mortality rate of the disease. Histopathological findings and whole transcriptome studies implicate aberrant vascular smooth muscle cell (SMC) function and fibrosis as key drivers of cardiovascular disease in post-COVID-19 patients. Remdesivir was the first antiviral drug approved for the treatment of COVID-19. While remdesivir improves clinical outcome of hospitalized patients with COVID-19, its actions on the vasculature are largely unknown. Accordingly, the present study investigated the effect of remdesivir on vascular SMC function. Treatment of human or rat aortic SMCs with remdesivir resulted in a concentration-dependent inhibition of cell proliferation and DNA synthesis. The antiproliferative action of remdesivir was observed at a clinically relevant concentration (10µM), occurred in the absence of cell death, and was associated with the arrest of SMCs in the G 0 /G 1 phase of the cell cycle. In addition, remdesivir attenuated the migration of vascular SMCs and the synthesis of collagen by these cells. Remdesivir also stimulated the expression of heme oxygenase-1 (HO-1). The induction of HO-1 by remdesivir was abrogated by mutating the antioxidant responsive elements of the HO-1 promoter, overexpressing dominant-negative Nrf2, or by inhibiting reactive oxygen species (ROS) production. Furthermore, silencing HO-1 expression partially rescued the proliferative, migratory, and synthetic response of remdesivir-treated SMCs, and this could be reversed by the exogenous administration of bilirubin or carbon monoxide. In conclusion, this study identifies remdesivir as a novel inhibitor of vascular SMC function. Moreover, it shows that remdesivir stimulates HO-1 expression via the ROS-Nrf2 signaling pathway, and that the induction of HO-1 blocks the activation of SMCs by generating bilirubin and carbon monoxide. The ability of remdesivir to exert these pleiotropic effects on vascular SMCs may mitigate the development of occlusive vascular disease in patients with COVID-19. National Institutes of Health R01 HL149727 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.