SARS-CoV-2 Mediated Endothelial Dysfunction: The Potential Role of Chronic Oxidative Stress

Abstract

Endothelial cells have emerged as key players in SARS-CoV-2 infection and COVID-19 inflammatory pathologies. Dysfunctional endothelial cells can promote chronic inflammation and disease processes like thrombosis, atherosclerosis, and lung injury. In endothelial cells, mitochondria regulate these inflammatory pathways via redox signaling, which is primarily achieved through mitochondrial reactive oxygen species (mtROS). Excess mtROS causes oxidative stress that can initiate and exacerbate senescence, a state that promotes inflammation and chronic endothelial dysfunction. Oxidative stress can also activate feedback loops that perpetuate mitochondrial dysfunction, mtROS overproduction, and inflammation. In this review, we provide an overview of phenotypes mediated by mtROS in endothelial cells – such as mitochondrial dysfunction, inflammation, and senescence – as well as how these chronic states may be initiated by SARS-CoV-2 infection of endothelial cells. We also propose that SARS-CoV-2 activates mtROS-mediated feedback loops that cause long-term changes in host redox status and endothelial function, promoting cardiovascular disease and lung injury after recovery from COVID-19. Finally, we discuss the implications of these proposed pathways on long-term vascular health and potential treatments to address these chronic conditions.

Biological and Clinical Factors contributing to the Metabolic Heterogeneity of Hospitalized Patients with and without COVID-19

“…67 In addition, circulating levels of arginine pathway metabolites can be affected by RBC arginase activity 45 , which is in turn affected by oxidant stress and can contribute to COVID-19-induced endotheliopathy. 40 Indole metabolites of microbial origin 68 were also signi cantly decreased in COVID-19 patients, especially in those with the poorest outcomes. These decreases may result from tryptophan depletion as a function of kynurenine pathway activation in COVID-19, 1,16,22,23 especially in older males.…”

“…1.J); also a hallmark of COVID-19-induced endotheliopathy. 40 Interestingly, other markers of endothelial coagulopathy were also signi cantly increased in COVID-19 patients (Figs. [1][2][3][4][5][6][7][8], including VWF and its collagen binding activity (p < 0.0001).…”

The zinc finger transcription factor, KLF2, protects against COVID-19 associated endothelial dysfunction

“…Since this discovery, 7 the importance of endothelial activation and dysfunction in COVID-19 has been intensively pursued. 8 , 18 , 23 , 26 More recently, increased markers of vascular inflammation, 27 oxidative stress, 28 EndoMT, 29 coagulation (D-dimer and plasminogen activator inhibitor-1), 15 , 30 immunothrombosis, 31 angiogenesis, 15 altered endothelial cell metabolism (glycolysis), 32 glycocalyx disruption 33 have been observed in patients with COVID-19 or SARS-CoV-2 spike protein treated endothelial cells (reviewed in ref. 9 ).…”

Mechanics Insights of Alpha-Lipoic Acid against Cardiovascular Diseases during COVID-19 Infection

“…Endothelial cells are heavily involved in COVID-19 pathology [ 4 ]. Thus, endothelial cells are a direct target of SARS-CoV-2 infection, and they also represent the starting point for the major disorders that accompany this infection [ 31 ].…”

“…COVID-19 has been associated with proinflammatory and prothrombotic conditions that can result in thromboembolic events; higher markers of thrombosis have been associated with worse clinical outcomes [ 3 ]. Additionally, in some situations patients have developed cardiovascular complications after recovery from COVID-19; the long-term consequences of SARS-CoV-2 infections are not yet fully known [ 4 ].…”