Endothelial Dysfunction, Inflammation, and Oxidative Stress in COVID-19-Mechanisms and Therapeutic Targets

Abstract

The outbreak of the COVID-19 pandemic represents an ongoing healthcare emergency responsible for more than 3.4 million deaths worldwide. COVID-19 is the disease caused by SARS-CoV-2, a virus that targets not only the lungs but also the cardiovascular system. COVID-19 can manifest with a wide range of clinical manifestations, from mild symptoms to severe forms of the disease, characterized by respiratory failure due to severe alveolar damage. Several studies investigated the underlying mechanisms of the severe lung damage associated with SARS-CoV-2 infection and revealed that the respiratory failure associated with COVID-19 is the consequence not only of acute respiratory distress syndrome but also of macro- and microvascular involvement. New observations show that COVID-19 is an endothelial disease, and the consequent endotheliopathy is responsible for inflammation, cytokine storm, oxidative stress, and coagulopathy. In this review, we show the central role of endothelial dysfunction, inflammation, and oxidative stress in the COVID-19 pathogenesis and present the therapeutic targets deriving from this endotheliopathy.

Figure 1

Functions of vascular endothelium. Endothelium cells produced some vascular mediators/factors that accomplished the six major functions of normal endothelium (modulation of vascular permeability and vasomotor tone modulation, coagulation homeostasis, inflammation and immunity regulation, cell growth regulation, and oxidation of LDL cholesterol) by which the vascular homeostasis is maintained (adapted after [9]).

Figure 2

SARS-CoV-2 enters the human body by binding to ACE2. Activation of RAAS produced a cytokine storm, resulting in the secretion of proinflammatory cytokines/chemokines such as interleukins (ILs), interferon-gamma (IFN-γ), monocyte chemoattractant protein-1 (MCP1), and tumor necrosis factor-alpha (TNF-α). This storm produces a pleiades of phenomena which is associated with preexistent comorbidities that lead to an increase in disease severity (adapted after [31]).

Figure 3

Mechanisms of endothelial dysfunction, inflammation, oxidative stress, and therapeutic targets in SARS-CoV-2 infection. SARS-CoV-2 infection begins when its peak proteins are proteolytically prepared by TMPRSS2, allowing them to bind to ACE2 and initiate viral endocytosis in the EC. This increases the amount of binding of Ang II to AT1R, which in turn activates NADPH-oxidase and subsequently induces an increased production of ROS. These excess ROS mediate signaling pathways that increase the production of inflammatory cytokines (such as IL-1β, IL-6, and TNF), decrease the bioavailability of NO and PGI2, and induce endothelial cell apoptosis, leading to endothelial damage and dysfunction. Furthermore, the release of proinflammatory and prothrombotic factors can lead to vascular inflammation, platelet aggregation, and thrombosis. These interactions increase the risk of thrombosis and lung damage in people infected with SARS-CoV-2. ROS also induce an overflow of NETs. There may be several positive feedback loops between cytokines (TNF-α, IL-1β) and ROS production as well as between cytokines (TNF-α, IL-1β) and NET formation. ROS, NETs, and proteolytic enzymes released by activated neutrophils also contribute to organ damage and clotting in vessels. Therapeutic targets address SARS-CoV-2-induced feedback loops in EC. Although there have been many therapies proposed to stop the spread of the coronavirus pandemic, those described here address feedback loops involving endothelial dysfunction, oxidative stress, and inflammation. TMPRSS2: transmembrane protease, serine 2; ACE2: angiotensin-converting enzyme 2; AT1R: angiotensin type 1 receptor; ROS: reactive oxygen species; c-Src: protooncogene tyrosine-protein kinase Src; PKC: protein kinase C; IL: interleukin; TNF: tissue necrosis factor; NO: nitric oxide; PGI2: prostaglandin I2 (also known as prostacyclin).