ABSTRACT
COVID19 patients with severe infection have been observed to have elevated autoantibodies (AAs) against angiotensin II receptor type 1 (AT1R) and endothelin (ET) 1 receptor type A (ETAR), compared with healthy controls and patients with favorable (mild) infection. AT1R and ETAR are G proteincoupled receptors, located on vascular smooth muscle cells, fibroblasts, immune and endothelial cells, and are activated by angiotensin II (Ang II) and ET1 respectively. AAs that are specific for these receptors have a functional role similar to the natural ligands, but with a more prolonged vasoconstrictive effect. They also induce the production of fibroblast collagen, the release of reactive oxygen species and the secretion of proinflammatory cytokines (including IL6, IL8 and TNFα) by immune cells. Despite the presence of AAs in severe COVID19 infected patients, their contribution and implication in the severity of the disease is still not well understood and further studies are warranted. The present review described the major vascular homeostasis systems [ET and reninangiotensinaldosterone system (RAAS)], the vital regulative role of nitric oxide, the AAs, and finally the administration of angiotensin II receptor blockers (ARBs), so as to provide more insight into the interplay that exists among these components and their contribution to the severity, prognosis and possible treatment of COVID19.
Subject(s)
COVID-19 , Vascular Diseases , Angiotensin II , Angiotensin Receptor Antagonists , Angiotensin-Converting Enzyme Inhibitors , Collagen , Endothelial Cells , Endothelins , Humans , Interleukin-6 , Interleukin-8 , Nitric Oxide , Reactive Oxygen Species , Receptor, Angiotensin, Type 1 , Receptor, Endothelin A , Receptors, Angiotensin , Tumor Necrosis Factor-alphaABSTRACT
COVID-19 pandemic has changed the world dramatically since was first reported in Wuhan city, China [1]. Not only as a respiratory illness that could lead to fatal respiratory failure, but also some evidences suggest that it can propagate as a chronic disease associated with a variety of persistent post COVID-19 pathologies that affect patients' life [2,3]. Pulmonary hypertension (PH) is one of the challenging diseases that may develop as a consequence of SARS-COV-2 infection in some COVID-19 survivors [4,5]. The vasopressor, proliferative, proinflammatory, and prothrombotic actions of endothelin [6] may be encountered in the COVID-19-induced PH pathology. And so, endothelin blockers may have an important role to restrict the development of serious PH outcomes with special precautions considering patients with significant hypoxemia.
Subject(s)
COVID-19 , Endothelins , Hypertension, Pulmonary , COVID-19/complications , Humans , Hypertension, Pulmonary/virology , PandemicsABSTRACT
The novel coronavirus 2019 (COVID-19) infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global pandemic that requires a multi-faceted approach to tackle this unprecedent health crisis. Therapeutics to treat COVID-19 are an integral part of any such management strategy and there is a substantial unmet need for treatments for individuals most at risk of severe disease. This perspective review provides rationale of a combined therapeutic regimen of selective endothelin-A (ET-A) receptor antagonism and sodium glucose co-transporter-2 (SGLT-2) inhibition to treat COVID-19. Endothelin is a potent vasoconstrictor with pro-inflammatory and atherosclerotic effects. It is upregulated in a number of conditions including acute respiratory distress syndrome and cardiovascular disease. Endothelin mediates vasocontractility via endothelin (ET-A and ET-B) receptors on vascular smooth muscle cells (VSMCs). ET-B receptors regulate endothelin clearance and are present on endothelial cells, where in contrast to their role on VSMCs, mediate vasodilation. Therefore, selective endothelin-A (ET-A) receptor inhibition is likely the optimal approach to attenuate the injurious effects of endothelin and may reduce ventilation-perfusion mismatch and pulmonary inflammation, whilst improving pulmonary haemodynamics and oxygenation. SGLT-2 inhibition may dampen inflammatory cytokines, reduce hyperglycaemia if present, improve endothelial function, cardiovascular haemodynamics and cellular bioenergetics. This combination therapeutic approach may therefore have beneficial effects to mitigate both the pulmonary, metabolic and cardiorenal manifestations of COVID-19. Given these drug classes include medicines licensed to treat heart failure, diabetes and pulmonary hypertension respectively, information regarding their safety profile is established. Randomised controlled clinical trials are the best way to determine efficacy and safety of these medicines in COVID-19.
Subject(s)
COVID-19 , Endothelin Receptor Antagonists , Endothelial Cells/metabolism , Endothelin-1/metabolism , Endothelins , Glucose , Humans , SARS-CoV-2 , Sodium , Sodium-Glucose Transporter 2ABSTRACT
We summarize the role of endothelin as a potent vasoconstrictor, pro-inflammatory, pro-oxidative agent in the pathophysiologic effects and end-organ dysfunction of coronavirus disease 2019 (COVID-19). Endotheliitis is an under-recognized pathophysiologic process that causes various types of dysfunction in end organs, including heart, lung, kidney, and brain. Endothelin receptor blockers, such as bosentan and sitaxentan, can pave a path ahead in the realm of COVID-19 therapies. These agents have a potential role against COVID-19 and should be studied in research trials to determine their efficacy in treatment of this severe disease.