Cardiovascular Dysfunction in COVID-19: Association Between Endothelial Cell Injury and Lactate

Abstract

Coronavirus disease 2019 (COVID-19), an infectious respiratory disease propagated by a new virus known as Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has resulted in global healthcare crises. Emerging evidence from patients with COVID-19 suggests that endothelial cell damage plays a central role in COVID-19 pathogenesis and could be a major contributor to the severity and mortality of COVID-19. Like other infectious diseases, the pathogenesis of COVID-19 is closely associated with metabolic processes. Lactate, a potential biomarker in COVID-19, has recently been shown to mediate endothelial barrier dysfunction. In this review, we provide an overview of cardiovascular injuries and metabolic alterations caused by SARS-CoV-2 infection. We also propose that lactate plays a potential role in COVID-19-driven endothelial cell injury.

Keywords: COVID-19; HMGB1 (High mobility group box 1); aerobic glycolytic metabolism; cardiovascular dysfunction; endothelial cell; lactate; thrombosis; vascular permeability.

Figure 1

Proposed model of aerobic glycolysis activation in SARS-CoV-2 infected endothelial cells. SARS-CoV-2 infection of pulmonary tissues leads to hypoxia. SARS-CoV-2 infection also causes mitochondrial dysfunction and reactive oxygen species (ROS) production in endothelial cells. Both hypoxia and ROS mediate HIF-1 stabilization. Enzymes involved in glycolysis, including hexokinase (HK), pyruvate kinase 2 (PKM2), lactate dehydrogenase (LDH) are upregulated by HIF-1 signaling, resulting in increased lactate production and SARS-CoV-2 replication in endothelial cells.

Figure 2

Proposed model of endothelium permeability induced by lactate/GPR81 signaling and SARS-CoV-2 infection. SARS-CoV-2 infection promotes the release of the pro-inflammatory cytokine IL-1β. IL-1β suppresses cAMP formation and CREB-mediated transcription of VE-cadherin in endothelial cells. SARS-CoV-2 infection also increases lactate production. Lactate activates GPR81 and reduces cAMP generation and CREB-mediated transcription of VE-cadherin in endothelial cells. In addition, SARS-CoV-2 spike proteins directly disorganize VE-cadherin complex and suppress VE-cadherin transcription in endothelial cells. Disruption of VE-cadherin complex is responsible for vascular permeability in COVID-19.

Figure 3

Proposed model of platelet activation, thrombosis and endothelial cell injury induced by SARS-CoV-2 infection and lactate. Binding of SARS-CoV-2 spike protein to ACE2 leads to MAPK signaling activation and subsequent platelet activation. Activated platelets release coagulation factors and cytokines to promote thrombosis. Internalization of SARS-CoV-2 virions induces the release of extracellular vesicles from platelets to facilitate thrombosis. In addition, lactate (acidity) also contributes to thrombosis by promoting activation of platelets, endothelial cells, and NETs.

Figure 4

Proposed model of HMGB1 release in SARS-CoV-2 infection. SARS-CoV-2 infection causes death of epithelial cells and release of HMGB1. Lactate, derived from aerobic glycolysis, also promotes HMGB1 acetylation and release from macrophages/monocytes. Elevated levels of HMGB1 further promotes inflammatory responses, ACE2 expression, endothelium permeability and thrombosis in COVID-19.