Coronavirus disease 2019 (COVID-19) is defined as an infectious respiratory disease propagated by a new virus labeled the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). COVID-19 was first identified in Wuhan, China in November of 2019 and has become a global health threat affecting more than 200 million people with a mortality rate of 2.3% due to its high contagiousness and lack of specific antiviral treatments (1). There are excellent reviews and articles on the clinical manifestation, hematology laboratory, and management of COVID-19 patients (1–3). By November 2021, over twenty COVID-19 vaccines have been approved in different parts of the world (4). Despite the COVID-19 vaccine, which has been quickly and successfully developed and employed to fight against the COVID-19 infection, the exact mechanisms by which the SARS-CoV-2 significantly causes dysfunction of several systems, including respiratory system, nerve system, and cardiovascular system have not been elucidated entirely.

Emerging clinical data has shown that the COVID-19 patients with cardiovascular diseases (CVDs) have a greater mortality (11%) than in total case mortality (2.3%) (5). On the other hand, COVID-19 infected patients exhibit cardiovascular disorders and heart attack symptoms (6–8). This evidence suggests that SARS-CoV-2 infection could cause cardiovascular dysfunction which is a major factor contributing to the mortality of a substantial proportion of the patients with severe COVID-19 infection. Importantly, the symptoms of severe COVID-19 infected patients resemble the clinical features of endothelial dysfunction (8, 9), indicating that SARS-CoV-2 could cause the endothelium damage. Indeed, electron microscopy analysis of post-mortem tissues showed that SARS-CoV-2 could infect pulmonary endothelial cells and induce endotheliitis in COVID-19 infected patients who are critically ill (9). In addition, SARS-CoV-2 could directly infect endothelial cells via angiotensin-converting enzyme 2 (ACE2), subsequently alter the vascular homeostasis, and induce clinical manifestations such as acute respiratory distress syndrome (ARDS) (9–11).

Recent studies highlight the role of metabolisms in the regulation of innate immune and inflammatory responses (12–15). Metabolic reprograming plays a critical role in innate immune and inflammatory responses (16). Severe COVID-19 infected patients usually exhibit the “cytokine storm”, indicating that the metabolisms in these patients have been altered. It is possible that aerobic glycolytic metabolism could be involved in the pathogenesis of the COVID-19 infection that induces severe conditions in those who are infected (17). Importantly, aerobic glycolytic metabolism not only regulates innate immune response (12), but also modulates endothelial cell function (14, 18). Generally, virus infections activate several immune cell types, such as dendritic cells, neutrophils and macrophages to produce pro-inflammatory cytokines that fight against virus invasions and maintain the tissues’ homeostasis (19). This process requires a rapid energy production to provide fuel for immune cell proliferation and inflammation (20). Recent evidence has shown that aerobic glycolytic metabolism and subsequent lactate production can be considered as an integral part of cellular signaling (12–14, 21). Furthermore, more recent findings in immunometabolism show that aerobic glycolysis can be a metabolic choice of immune cells and the function of aerobic glycolytic metabolism is not limited to supporting cell proliferation (22). Thus, it appears that cells can modulate their metabolism to adapt to different energy requirements and signaling events in pathophysiological situations.

Historically, lactate was the end product of aerobic glycolytic metabolism and was considered as a “waste” to be cleared from blood by the liver and kidney (23). Growing evidence suggests that lactate can be used as a sensitive and independent biomarker for critical illnesses, including sepsis (24), cardiovascular dysfunction (25, 26) and various types of cancer (27). Lactate could be a potent signaling molecule in vascular homeostasis, which is supported by a study showing that lactate disrupts vascular barrier function and increases vascular permeability of bone marrow during inflammation (14). Moreover, lactate dehydrogenase (LDH), a key enzyme in aerobic glycolysis, has been associated with worse outcomes in patients with viral infections, including COVID-19 (28–31). In addition, serum lactate levels in severe COVID-19 infected patients are significantly increased (32–35), suggesting increased aerobic glycolytic metabolism in COVID-19 infected patients (17). The important question is whether the COVID-19 infection alters cellular metabolisms that contribute to cardiovascular dysfunction. Based on current knowledge that aerobic glycolytic metabolism is involved in metabolic immune function (36) and cardiovascular dysfunction (37), understanding of the potential mechanisms by which SARS-CoV-2 causes endothelial cell barrier dysfunction could provide preventative and therapeutic solutions for severe COVID-19 patients. In this review, we summarize the association between the COVID-19 infection and cardiovascular dysfunction and discuss the potential role of aerobic glycolytic metabolism and SARS-CoV-2 induced endothelial cell barrier dysfunction, leading to multiple organ damage.

The endothelium is a layer of endothelial cells (ECs) that line the interior surface of blood vessels and plays a critical role in mediating vasomotor tone, maintaining blood fluidity, and balancing local inflammatory mediators (65, 66). The maladaptive response of ECs to acute inflammation contributes to the pathogenesis of various infectious diseases and multiple organ dysfunction syndrome (MODS) (67). Several recent studies investigated mechanisms by which SARS-Cov-2 induces EC dysfunctions, including inflammation, vasoconstriction, permeability, and coagulation (68–70). A study by Ackermann et al. shows that COVID-19 infection not only causes acute respiratory distress syndrome (ARDS), but also harms the vasculature (71). This pathologic study included seven lung tissues from COVID-19 infected patients, seven lungs from Influenza (H1N1) patients with ARDS, and 10 from age-matched uninfected controls. These lung tissues were examined with seven-color immunohistochemical analysis, micro-computed tomographic imaging, scanning electron microscopy, corrosion casting, and direct multiplexed measurement of gene expression. The authors compared the results between the groups focusing on the three distinct angiocentric features including: 1) severe endothelial injury associated with intracellular SARS-CoV-2 virus and disrupted endothelial cell membranes, 2) widespread vascular thrombosis with microangiopathy and occlusion of alveolar capillaries, and 3) significant new vessel growth through a mechanism of intussusceptive angiogenesis. The COVID-19 infected patients exhibited 9 times more alveolar capillary microthrombi (P<0.001) compared with H1N1 influenza patients. COVID-19 infected patients also presented with 2.7 greater of the amount of new vessel growth through intussusceptive angiogenesis (P<0.001) than in H1N1 influenza. In addition, endothelial cells from the COVID-19 patients exhibited cellular swelling, disrupted intracellular junctions, and a loss of contact with the basement membrane. An in vitro study by Robles and colleagues showed that the spike protein of SARS-CoV-2 promotes the expression of leukocyte adhesion molecules VCAM1 and ICAM1 upon binding to integrin α5β1 on ECs, resulting in increased leukocyte adhesion to ECs (72). A previous study shows that integrin α5β1 activates NF-κB in ECs to elicit inflammation (73). Consistently, SARS-CoV-2 protein treatment enhanced p65 nuclear accumulation and IL-6 expression in ECs (72, 74). To explore the mechanism of myocardial injury in COVID-19 infected patients, Feng et al. utilized a rhesus macaque model of SARS-CoV-2 respiration tract infection (75). They observed that increased infiltration of inflammatory cells in left ventricle tissues and elevated levels of inflammatory cytokines in infected macaques, suggesting the occurrence of viral myocarditis following SARS-CoV-2 infection (75). Notably, the expression of ICAM1 and VCAM1 in the left ventricle tissues was also upregulated in infected macaques as compared to healthy controls (75). These findings provided evidence showing that the endothelial cell damage may be attributed to direct SARS-CoV-2 infection and perivascular inflammation.

Angiotensin-Converting Enzyme 2 (ACE2) is a type-I transmembrane glycoprotein that negatively regulates the renin-angiotensin system (RAS) by degrading Ang II to the heptapeptide Ang 1-7 (76, 77). The protein was initially identified as a homolog to ACE in 2000 by Tipnis et al. (78). Besides its peptidase-dependent actions in regulating RAS, ACE2 was then identified as an essential receptor for SARS coronavirus in 2003 (79). Although ACE2 is shown as a protective molecule against lethal lung injury in SARS, the expression of ACE2 is not limited to respiratory system (80). Instead, a recent immunohistochemical analysis showed that ACE2 has limited expression in respiratory tracts compared to other tissues/cells, including enterocytes, renal tubules, gallbladder, cardiomyocytes, male reproductive cells, placental trophoblasts, ductal cells, eye, and vasculature (76). Intriguingly, ACE2 is expressed in arterial and venous endothelial cells and arterial smooth muscle cells in various human organs (81). It is suggested that ACE2 is required to maintain the endothelial integrity inside the vessels (11). Indeed, existing data for SARS-CoV-1 in 2002 SARS pandemic indicate that virus binding can reduce ACE2 levels, which may lead to endothelial dysfunction (80).

Recent evidence suggests that ACE2 is a functional receptor for SARS-CoV-2 to enter host target cells (82, 83). The infection of SARS-CoV-2 begins with SARS-CoV-2 cleaving its S protein through transmembrane protease serine 2 (TMPRSS-2) and attaching to the ACE-2 receptor (84–86). This ongoing infection produces significant endotheliitis, a robust immune response and a subsequent increase in pro-inflammatory cytokines, vasoactive molecules, and immune cells like neutrophils, macrophages, monocytes, and lymphocytes which all play a role in propagating a response known as the cytokine storm (71, 84, 87, 88). In vitro study using engineered human blood vessel organoids showed that SARS-CoV-2 can directly infect endothelial cells via ACE2 (89). Varga et al. reported that the presence of viral inclusion structures was detected in endothelial cells in COVID-19 patients (9). Intriguingly, neutralization of ACE2 using soluble human ACE2 decreased virus-infected endothelial cells in vivo (89). These pieces of evidence highlight the role of ACE2 in mediating of SARS-CoV-2 induced endothelial cell injury. Indeed, the endothelium is a vulnerable target by SARS-CoV-2 infection, and these infected endothelial cells exhibit dramatic changes in morphology and function (71). Therefore, endothelial cell dysfunction could be an important and potential pathogenesis of COVID-19 infection induced multiple organ dysfunction. In the following sections, we step beyond our focus on the virus and discuss the role of aerobic glycolytic metabolism in COVID-19-driven endothelial cell injury in order to better understand the potential mechanisms that cause the endothelial cell damage in COVID-19 infected patients.

Previous studies have shown that virus infection dramatically modified the cellular metabolism of host cells (90). It is hypothesized that the virus-driven metabolic process in a host cell is to provide macromolecules needed for virion replication and assembly (20, 90). Thomas et al. observed that the levels of glucose and free fatty acid in the serum of COVID-19 infected patients were significantly increased providing fuels for viral proliferation (91). Similarly, Shen et al. reported that the serum glucose levels were elevated in the severe patients infected with COVID-19, when compared with control groups (92). In addition, patients with pre-existing metabolic diseases, including diabetes, have greater risk of developing severe conditions (93). A study including 174 COVID-19 infected patients implies that diabetic patients without other comorbidities were at high risk of severe pneumonia, excessive inflammation responses and hypercoagulable state (94). To understand the potential mechanism by which uncontrolled diabetes is a risk factor for severe COVID-19, Codo et al. investigated the correlation between glycolysis and SARS-CoV-2 replication and found that glucose enhanced SARS-CoV-2 load in monocytes in a dose dependent manner (95). In agreement, a retrospective observational study, including 2433 COVID-19 patients admitted to the Houshen Shan hospital in Wuhan between February and April in 2020, indicates that elevated glucose level could be a predictive maker for the disease progression and the fatality of COVID-19 patients (96). Moreover, He et al. reported that COVID-19 infected patients without pre-existing diabetes also presented high blood glucose levels (97), indicating that SARS-CoV-2 infection may change metabolic profiles in these patients. Indeed, most viruses tested to date can induce aerobic glycolytic metabolism to favor their replication (20), which seems to be the same case for SARS-CoV-2 infection. Thus, when the virus enters a diabetic patient, especially a Type II diabetic patient, the high glucose levels within the host results in a disrupted glucose metabolism. This disruption favors SARS-CoV-2 replication and cytokine production while simultaneously dampening the proper effects of the immune system (T-cell response/function is worsened), prompting a more severe inflammatory response (cytokine storm) within this demographic (95).

Mitochondria are essential cellular organelles in regulating cellular energy, metabolism, and host innate immunity (98–100). Transcriptomic study by Mooamalla et al. shows that SARS-CoV-2 infection downregulated tricarboxylic acid cycle (TCA) and oxidative phosphorylation in several human respiratory cell lines, indicating mitochondrial dysfunction (101). Indeed, emerging evidence shows that SARS-CoV-2 highjacks mitochondria and replicates in mitochondria, leading to impaired mitochondrial dynamics and cell death (102). It is proposed that aerobic glycolytic metabolism is enhanced when mitochondrial defect occurs (103, 104). Mooamalla and colleagues also found that the expression of lactate dehydrogenase (LDHA), which is a dispensable enzyme for aerobic glycolysis, was increased and lactate production was elevated in SARS-CoV-2-infected human respiratory cell lines (101). Notably, similar observation is made in peripheral blood mononuclear cells (PBMCs) isolated from COVID-19 patients, in which the rate of glycolysis was increased, and the mitochondrial respiration was impaired (105).

It has been reported that SARS-CoV-2 affects both the upper and lower respiratory tract, which, in many cases, results in hypoxemia (106, 107). In addition to virus-driven metabolic changes, lack of oxygen may also be a determinant in regulating metabolism in patients with COVID-19 infection. Inadequate oxygen supply shifts oxidative phosphorylation to aerobic glycolysis, leading to increased production of lactate and extracellular acidification. It is demonstrated that lactate is a natural suppressor for antiviral signaling though inhibiting retinoic acid-inducible gene (RIG) (21). Collectively, COVID-19 infection could induce a metabolic switch from oxidative phosphorylation to aerobic glycolysis which does not only benefit to virus replication, but also priming innate immunity mediated pro-inflammatory cytokine production (95, 108). In addition, the intermediates of aerobic glycolytic metabolism could play an important role in the regulation of pro-inflammatory response and endothelial cell dysfunction (12, 14).

As mentioned above, growing evidence shows that COVID-19 infection switches metabolisms from oxidative phosphorylation to aerobic glycolytic metabolism (17, 105), which allows the rapid production of energy and other substrates for viral replication (20). Lactate is the end product of aerobic glycolysis and serves as an important diagnostic biomarker for critical illnesses, such as sepsis/septic shock (24). It has been shown that severe COVID-19 patients developed typical symptoms that are similar to septic shock, such as vascular microthrombosis, multi-organ dysfunction syndrome (MODS), coagulopathy, high cytokine production (109). Considering the parallels in the pathophysiology of sepsis and COVID-19, it is proposed that viral sepsis is crucial to the pathogenetic mechanisms of COVID-19 (110). In this case, lactate generated from aerobic glycolytic metabolism may be also applied as a biomarker for diagnosis and prognosis of COVID-19 infected patients. Velavan et al. showed that hospitalized patients with moderate to severe COVID-19 (N = 18) had significantly higher blood lactate levels than mild ambulatory COVID-19 patients (N = 16) (33). In addition, a retrospective study including 45 ICU-admitted patients with COVID-19 showed that sequential organ failure assessment (SOFA) score and initial blood lactate levels were significantly higher in non-survivors (N = 11) compared to survivors (N = 34), indicating that blood lactate level mirrors organ dysfunction and is associated with poor clinical outcomes of COVID-19 ICU patients (32). In consistent with this observation, Metkus et al. reported that non-survivors (N = 88) had significantly elevated blood lactate levels than survivors (N = 155) of COVID-19 patients (3.6 mmol/L vs. 2.0 mmol/L, P = 0.005) (111). Moreover, blood lactate levels positively and independently correlate with troponin (troponin I or troponin T) levels in COVID-19 patients (N = 243, P = 0.007), suggesting that lactate may serve as predictor for myocardia injury in COVID-19 patients (111). These pieces of evidence suggest that elevated lactate levels could correlate with both severity and mortality of COVID-19. Of note, a pooled analysis, including 1,532 COVID-19 patients, reported that increased lactate dehydrogenase (LDH) levels were associated with a 6-fold increase in odds of severe COVID-19 and 16-fold increase in odds of COVID-19 mortality (112). Given that LDH is involved in lactate production, it is advisable that lactate consumption might be also increased.

Although lactate was considered as a waste in the past decades (23), growing evidence has shown that lactate may exert important regulatory roles in various pathophysiological processes, including immunosuppression (12, 113–115), cell signaling (13, 116) and gene transcription (117–119). Recent studies further reveal that lactate can directly induce permeability in inflammatory bone marrow endothelium by downregulation of VE-cadherin expression (14), indicating that lactate could contribute to the pathophysiologic mechanisms of cardiovascular injury in COVID-19 infection. As a result, the implication of serum lactate may be able to present us with an improved method of measuring clinical severity and observe clinical treatment response in the context of COVID-19. In the sections below, we discuss the possible mechanisms of lactate-mediated endothelial injuries in the pathogenesis of COVID-19 infection.

SARS-CoV-2 infection causes metabolic reprogramming, such as increased glucose consumption and lactate production, which plays a role in the severity and mortality of COVID-19. Lactate is not only a valuable biomarker but also a critical signaling molecule in critical illness, including COVID-19. Thus, it is proposed that both reduced lactate production and inhibition of lactate-mediated signaling could improve COVID-19 (194). In this context, application of glycolysis inhibitors, such as 2-deoxy-D-glucose (2-DG), may have beneficial effects on COVID-19-infected patients. 2-DG is a glucose analogue which competitively inhibits the production of glucose-6-phosphate and consequently suppresses the glycolytic pathway (195). Our previous studies have demonstrated that at non-toxic dosages 2-DG markedly decreased lactate production and improved cardiac function in polymicrobial sepsis mice (196). Notably, the emergent use of 2-DG as an adjunct therapy in COVID-19 patients has been granted in India (197). In addition, animal studies show that lactate activates GPR81, a lactate specific receptor, to promote endothelial injury and immune cell dysfunction, which can be reversed by GPR81 inhibitors (12–14). Lactate can also be taken up by various cells through monocarboxylate transporter 1 (MCT1) (13, 198). We recently reported that blocking lactate influx by MCT1 inhibitor, as well as suppression of GPR81 signaling, decreased HMGB1 release from macrophages (13). Therefore, similar therapeutic strategies, either inhibition of lactate/GPR81 signaling or block lactate influx by MCT inhibitors, could also be used to abolish the detrimental effects of lactate in SARS-CoV-2 infection (194). On the other hand, priming the immune system with immunomodulatory components such as glucans may protect cardiovascular dysfunction in COVID-19. HMGB1 is a potential biomarker and may serve as a therapeutic target in severe COVID-19 (175). Our group previously reported that glucan phosphate improved cardiac function and suppressed HMGB1 translocation to the cytoplasm during sepsis (199, 200). This mode of action of glucan may counteract the effect of lactate in promoting HMGB1 release during SARS-CoV-2 infection (13). Importantly, a recent study has shown that glucans and mannans can be used as adjuvants to enhance the magnitude and durability of COVID-19 vaccines (201–203).

Since the outbreak of COVID-19, significant effort has been made to understand the pathogenesis of this new disease. With evidence collected from histological studies and biomedical tests, there has been increasing recognition that endothelial cell injury is one of the major contributors to the severity and mortality of COVID-19 infected patients. Recent evidence highlights the role of metabolism switching in the regulation of innate immune and inflammatory responses, which is observed in COVID-19 infected patients (204, 205). This review summarizes the potential role of aerobic glycolysis-derived lactate in the COVID-19 infection. In this mechanism of infection, lactate serves as an mediator that facilitates SARS-CoV-2 infection of endothelial cells, which leads to endothelial cell injury and multiple organ dysfunction. It is clear that growing evidence shows that lactate is involved in SARS-CoV-2-mediated endothelial cell death, vascular permeability, and coagulopathy. On the other hand, elevation of lactate levels, due to enhanced glycolysis, could also contribute to endothelial injury by altering immune cell function. Further basic science research is needed to validate whether targeting aerobic glycolytic metabolism could be beneficial for patients with COVID-19 infection.

KY, MH, MF, VL, YY were involved in the literature search, and drafting and preparation of the manuscript. KY, CL and XW were involved in the idea generation. KY, TH and DW were involved in checking the manuscript. All authors contributed to the article and approved the submitted version.

This work was supported by National Institutes of Health grants HL071837 (CL), HL153270 (CL), GM083016 (CL, DW), GM119197 (DW), American Heart Association Postdoctoral Fellowship 916710 (MF), and C06RR0306551 (ETSU).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.