The effects of hydroxychloroquine on endothelial dysfunction

Rahman, Raha Abdul; Murthi, Padma; Singh, Harmeet; Gurusinghe, Seshini; Mockler, Joanne C.; Lim, Rebecca; Wallace, Euan M.

doi:10.1016/j.preghy.2016.09.001

Cited by 43 publications

(37 citation statements)

References 25 publications

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“…Hydroxychloroquine had no effect on modulating hypoxia-induced placental injury. These findings support those of others who tested hydroxychloroquine in a trophoblast-derived cell line exposed to antiphospholipid antibodies as a model of antiphospholipid syndrome [26]. They found that although hydroxychloroquine was able to mitigate trophoblast secretion of IL-6, it had no effect on sEng release [26].…”

Section: Discussionsupporting

confidence: 89%

“…These findings support those of others who tested hydroxychloroquine in a trophoblast-derived cell line exposed to antiphospholipid antibodies as a model of antiphospholipid syndrome [26]. They found that although hydroxychloroquine was able to mitigate trophoblast secretion of IL-6, it had no effect on sEng release [26]. Collectively, this suggests that in an established diagnosis of preeclampsia, the use of hydroxychloroquine may not confer any beneficial effects.…”

Section: Discussionsupporting

confidence: 86%

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Hydroxychloroquine Mitigates the Production of 8-Isoprostane and Improves Vascular Dysfunction: Implications for Treating Preeclampsia

Rahman

Murthi

Singh

et al. 2020

IJMS

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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.

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Section: Discussionsupporting

confidence: 89%

Section: Discussionsupporting

confidence: 86%

Hydroxychloroquine Mitigates the Production of 8-Isoprostane and Improves Vascular Dysfunction: Implications for Treating Preeclampsia

Rahman

Murthi

Singh

et al. 2020

IJMS

Self Cite

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“…Even the antimalaric agents chloroquine and hydroxychloroquine, initially proposed as a therapy for COVID-19 based on anecdotal data [229,236], have been shown to improve endothelial function [237,238]. If our theory is correct [239], other drugs that might be effective in treating COVID-19 patients through their beneficial effects on endothelial cells include α1 adrenergic receptor blockers (e.g., doxazosin) [240], modulators of Sigma receptors [241][242][243], metformin [244], indomethacin [245], and endothelin receptor antagonists (e.g., bosentan) [246].…”

Section: Anticoagulation As a Key Therapy For Covid-19mentioning

confidence: 99%

Hypertension, Thrombosis, Kidney Failure, and Diabetes: Is COVID-19 an Endothelial Disease? A Comprehensive Evaluation of Clinical and Basic Evidence

Sardu

Gambardella

Morelli

et al. 2020

JCM

469

436

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The symptoms most commonly reported by patients affected by coronavirus disease (COVID-19) include cough, fever, and shortness of breath. However, other major events usually observed in COVID-19 patients (e.g., high blood pressure, arterial and venous thromboembolism, kidney disease, neurologic disorders, and diabetes mellitus) indicate that the virus is targeting the endothelium, one of the largest organs in the human body. Herein, we report a systematic and comprehensive evaluation of both clinical and preclinical evidence supporting the hypothesis that the endothelium is a key target organ in COVID-19, providing a mechanistic rationale behind its systemic manifestations.

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“…103,104 Also, the vasodilatory effect of the drug sildenafil was shown in a randomized control trial to be ineffective in preventing severe FGR in high-risk women. 118 Additional drugs with potential to prevent severe preeclampsia, and therefore potentially any associated FGR, include proton pump inhibitors, 119 statins, 120 metformin, 121 hydroxychloroquine, 122 and melatonin. 123 With the exception of melatonin, none have been shown to prevent FGR.…”

Section: Expert Reviews Ajogorgmentioning

confidence: 99%

A placenta clinic approach to the diagnosis and management of fetal growth restriction

Kingdom

Audette

Hobson

et al. 2018

American Journal of Obstetrics and Gynecology

135

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Effective detection and management of fetal growth restriction is relevant to all obstetric care providers. Models of best practice to care for these patients and their families continue to evolve. Since much of the disease burden in fetal growth restriction originates in the placenta, the concept of a multidisciplinary placenta clinic program, managed primarily within a maternal-fetal medicine division, has gained popularity. In this context, fetal growth restriction is merely one of many placenta-related disorders that can benefit from an interdisciplinary approach, incorporating expertise from specialist perinatal ultrasound and magnetic resonance imaging, reproductive genetics, neonatal pediatrics, internal medicine subspecialties, perinatal pathology, and nursing. The accurate diagnosis and prognosis for women with fetal growth restriction is established by comprehensive clinical review and detailed sonographic evaluation of the fetus, combined with uterine artery Doppler and morphologic assessment of the placenta. Diagnostic accuracy for placenta-mediated fetal growth restriction may be enhanced by quantification of maternal serum biomarkers including placenta growth factor alone or combined with soluble fms-like tyrosine kinase-1. Uterine artery Doppler is typically abnormal in most instances of early-onset fetal growth restriction and is associated with coexistent preeclampsia and underlying maternal vascular malperfusion pathology of the placenta. By contrast, rare but potentially more serious underlying placental diagnoses, such as massive perivillous fibrinoid deposition, chronic histiocytic intervillositis, or fetal thrombotic vasculopathy, may be associated with normal uterine artery Doppler waveforms. Despite minor variations in placental size, shape, and cord insertion, placental function remains, largely normal in the general population. Consequently, morphologic assessment of the placenta is not currently incorporated into current screening programs for placental complications. However, placental ultrasound can be diagnostic in the context of fetal growth restriction, for example in Breus' mole and triploidy, which in turn may enhance diagnosis and management. Several examples are illustrated in our figures and supplementary videos. Recent advances in the ability of multiparameter screening and intervention programs to reduce the risk of severe preeclampsia will likely increase efforts to deliver similar improvements for women at risk of fetal growth restriction. Placental pathology is important because the underlying pathologies associated with fetal growth restriction have a wide range of recurrence risks. Rare conditions such as massive perivillous fibrinoid deposition or chronic histolytic intervillositis may recur in >50% of subsequent pregnancies. Postpartum care in a placenta-focused program can provide effective counseling for modifiable maternal risk factors, and can assist in planning future pregnancy care based on the pathologic basis of fetal growth restriction.

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The effects of hydroxychloroquine on endothelial dysfunction

Cited by 43 publications

References 25 publications

Hydroxychloroquine Mitigates the Production of 8-Isoprostane and Improves Vascular Dysfunction: Implications for Treating Preeclampsia

Hydroxychloroquine Mitigates the Production of 8-Isoprostane and Improves Vascular Dysfunction: Implications for Treating Preeclampsia

Hypertension, Thrombosis, Kidney Failure, and Diabetes: Is COVID-19 an Endothelial Disease? A Comprehensive Evaluation of Clinical and Basic Evidence

A placenta clinic approach to the diagnosis and management of fetal growth restriction

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