Endothelin receptor antagonists for pulmonary arterial hypertension and COVID-19: Friend or foe?

Coronavirus disease 2019 (COVID-19) poses a threat to individuals with chronic health conditions who are more likely to develop severe pneumonia and death. Those with pulmonary arterial hypertension represent such a high-risk group. Severe COVID-19 presents with respiratory failure secondary to immunopathologic injury likely due to a combination of direct cytopathic effects of the virus in concert with an aberrant immune response. The interplay between these 2 components has recently been better understood. Indeed, the severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) genome encodes 8 accessory proteins designated open reading frame (ORF) with identified functions. In particular, the ORF-3a protein initiates necroptosis once oligomerized by RIP3, allowing it to form a potassium-sensitive channel inserted into late endosomal, lysosomal, and trans-Golgi network membranes.¹ RIP3-driven oligomerization of ORF-3a plays a critical role in driving necrotic cell death, independent from and hijacking RIP3-MLKL necroptotic signaling. There is considerable evidence that an abundance of necroptosis perpetuates pathogenic inflammation and drives tissue injury.² Fatal cases of SARS-CoV-2 infection similarly show significant lung damage in response to inflammation, which may very well be driven by necroptosis.³ Endothelin (ET)-1 effects on cell survival and death may vary depending on the cell type, concentrations, and disease conditions. In contrast to low-physiologic doses, high levels of ET-1 usually trigger activation of necroptotic gene expression.⁴ For this reason, patients with pulmonary arterial hypertension may be prone to activate the necroptotic pathways. Furthermore, under inflammatory and endotoxemic stress conditions, as in SARS, ET-1‒mediated effects are shifted to promote necroptosis through a potent and long-lasting RIP-3 activation,^{4 , 5} thereby enhancing oligomerization of the ORF-3a protein and increasing the catastrophic effects of the proinflammatory necroptotic cell death on SARS-CoV-2 pathogenesis. Blocking of ET receptors with bosentan was able to inhibit the necroptosis pathway in experimental models of microvascular endothelial cells.⁵ As ET receptor antagonists counteract the vicious circle of ET-1‒mediated RIP-3 activation and propagation of the proinflammatory necroptotic cell death, as it happens in the worst form of SARS, we propose that it seems safe to continue ET receptor antagonists in patients on treatment with this class of drugs.