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Urgent Guidance for Navigating and Circumventing the QTc-Prolonging

and Torsadogenic Potential of Possible Pharmacotherapies for Coronavirus Disease 19 (COVID-19)

Int J Mol Sci. 2020 Apr 3;21(7) Hydroxychloroquine Mitigates the Production of 8-Isoprostane and Improves Vascular Dysfunction: Implications for Treating Preeclampsia. Rahman RA1,2,3, Murthi P2,4, Singh H2, Gurungsinghe S1, Leaw B2, Mockler JC1, Lim R1,2, Wallace EM1,2. Author information 1 Department of Obstetrics and Gynaecology, School of Clinical Sciences, Monash University, Monash Medical Centre, Clayton, Victoria 3168, Australia. 2 The Ritchie Centre, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia. 3 Department of Obstetrics and Gynaecology, Faculty of Medicine, National University of Malaysia, Kuala Lumpur 56000, Malaysia. 4 Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria 3052, Australia. Abstract In preeclampsia, widespread maternal endothelial dysfunction is often secondary to excessive generation of placental-derived anti-angiogenic factors, including soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), along with proinflammatory cytokines such as tumour necrosis factor-α (TNF-α) and activin A, understanding of which offers potential opportunities for the development of novel therapies. The antimalarial hydroxychloroquine is an anti-inflammatory drug improving endothelial homeostasis in lupus. It has not been explored as to whether it can improve placental and endothelial function in preeclampsia. In this in vitro study, term placental explants were used to assess the effects of hydroxychloroquine on placental production of sFlt-1, sEng, TNF-α, activin A, and 8-isoprostane after exposure to hypoxic injury or oxidative stress. Similarly, human umbilical vein endothelial cells (HUVECs) were used to assess the effects of hydroxychloroquine on in vitro markers of endothelial dysfunction. Hydroxychloroquine had no effect on the release of sFlt-1, sEng, TNF-α, activin A, or 8-isoprostane from placental explants exposed to hypoxic injury or oxidative stress. However, hydroxychloroquine mitigated TNF-α-induced HUVEC production of 8-isoprostane and Nicotinanamide adenine dinucleotide phosphate (NADPH) oxidase expression. Hydroxychloroquine also mitigated TNF-α and preeclamptic serum-induced HUVEC monolayer permeability and rescued the loss of zona occludens protein zona occludens 1 (ZO-1). Although hydroxychloroquine had no apparent effects on trophoblast function, it may be a useful endothelial protectant in women presenting with preeclampsia. KEYWORDS: TNF-α; endothelial dysfunction; hydroxychloroquine; preeclampsia; sEng; sFlt-1

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