The effects of hydroxychloroquine on endothelial dysfunction

Highlights

• Hydroxychloroquine reduces endothelin-1 release from endothelial cells.

• Hydroxychloroquine improves endothelial cell capillary formation in vitro.

• Hydroxychloroquine may be a useful adjuvant therapy for severe preeclampsia.

Abstract

Hydroxychloroquine is an anti-malarial drug which, due to its anti-inflammatory and immunomodulatory effects, is widely used for the treatment of autoimmune diseases. In a model of systemic lupus erythematosus hydroxychloroquine has been shown to exert protective endothelial effects. In this study, we aimed to investigate whether hydroxychloroquine was endothelial protective in an in vitro model of TNF-α and preeclamptic serum induced dysfunction. We showed that hydroxychloroquine significantly reduced the production of TNF-α and preeclamptic serum induced endothelin-1 (ET-1). Hydroxychloroquine also significantly mitigated TNF-α induced impairment of angiogenesis. These findings support the further assessment of hydroxychloroquine as an adjuvant therapy in preeclampsia.

Introduction

Preeclampsia is a multi-systemic disorder affecting about 5% of pregnancies [1]. It is associated with increased risks of maternal and perinatal mortality and morbidity and remains a leading cause of iatrogenic preterm birth [1], [2]. While the pathophysiology of preeclampsia is yet to be fully elucidated there is growing evidence that excessive placental and systemic oxidative stress and widespread maternal endothelial dysfunction are the two main pathologies contributing to the signs and symptoms of the clinical syndrome [1], [3], [4], [5], [6].

Specifically, it is currently thought that the endothelial dysfunction is, at least in part, secondary to excessive placental release of pro-inflammatory and anti-angiogenic factors, such as tumour necrosis factor-α (TNF-α), soluble fms-like tyrosine kinase-1 (sFlt-1), soluble endoglin (sEng) and activin A into the maternal circulation [6], [7], [8], [9], [10], [11], [12], [13]. In particular, women with established preeclampsia have significantly higher levels of TNF-α than women with a healthy pregnancy [13]. Maternal levels of TNF-α are also increased in other pregnancy complications associated with altered placental function such as fetal growth restriction and diabetes [14], [15]. It has been shown that TNF-α induces endothelial dysfunction with many of the features seen in women with preeclampsia including increased endothelin-1 (ET-1) release, down-regulated endothelial nitric oxide synthase (eNOS) expression, increased NADPH oxidase activity and impaired angiogenesis [16].

Systemic lupus erythematosus (SLE), an autoimmune disease, shares many features with preeclampsia including elevated levels of TNF-α and endothelial dysfunction [17], [18]. Recently, hydroxychloroquine, an antimalarial drug commonly used in the treatment of SLE, was shown to improve endothelial function in mice model of severe SLE [19]. Treatment with hydroxychloroquine is also associated with a decline in serum ET-1 levels in patients with SLE [20].

Accordingly, we aimed to determine whether hydroxychloroquine was able to mitigate the in vitro features of endothelial dysfunction induced by recombinant TNF-α or preeclamptic serum specifically to changes in endothelin-1 (ET-1) release and angiogenesis. To our knowledge, this is the first study to investigate the potential of hydroxychloroquine to improve TNF-α and preeclamptic serum induced endothelial dysfunction.