The SARS-CoV2 community-acquired pneumonia originates from complex interactions between biochemical and molecular factors. Recent studies have found that ACE2 is central in diseases affecting almost all organs and systems, including cardiac, respiratory, renal, and endocrine functions . It is the critical host cellular receptor of SARS-CoV-2. It has been identified in multiple organs, but its cellular distribution in the human heart is not illuminated clearly . The SARS-CoV-2 infection has several effects on the RAS, and conversely, regulation of this receptor may affect the disease's progression . Increased ACE activity with lungs insufficiency and ARDS provoke the processes of heart damage .
Some studies have reported an epidemiological association between a history of cardiac disease and worsened outcome during COVID infection [Bódi B et al., 2021]. The COVID patients with cardiac disease history or who acquire new cardiac injury are at an increased risk for in-hospital morbidity and mortality . More studies are needed to address the mechanism of cardiotoxicity and the treatments that can minimize permanent damage to the cardiovascular system .
The high rate of severe cases among COVID-19 patients with primary cardiovascular disease, and these results also perhaps provide essential re ference to clinical treatment of cardiac injury among severe patients infected by SARS-CoV-2 . Moreover, severe ARDS SARS-CoV-2 infects host cells through ACE2 receptors, leading to coronavirus disease (COVID-19)-related pneumonia while also causing acute myocardial injury and chronic damage to the cardiovascular system [36, 37].
AH is a multifactorial disease caused by environmental, metabolic, and genetic factors. It is little currently known about the complex interplay between the variety of factors and changes in blood pressure . The combined prevalence of AH and DM appears to confer the most significant risk. Arterial hypertension had a substantial impact on inpatient mortality. Social deprivation and ethnicity did not affect the patient once in hospital . The impaired blood pressure regulation was obtained in AH patients, where the growth in ACE activity was associated with nitrites' low level. The association of ACE and eNOS (endothelial NO synthase) genotype polymorphisms is known with risk of cardiovascular disorders , probably resulting in severe susceptibility AH patients to the COVID-19 infection.
Acute inflammation is a factor for the adverse outcome. The association between the ACE activity, NO ions presence, and troponin level is found. The RAS imbalance induced by the inflammation and accumulation of bradykinin impacts the patent’s outcome. Bradykinin is an essential part of the vasopressor system. It causes hypotension and vasodilation and is degraded by ACE, enhanced by the angiotensin produced by ACE2, and active the endothelial NO synthase followed by the NO ions release.
Another significant reason is a systemic inflammatory reaction with adipose-derived hormones and hyperglycemia as a specific SARS-COV2 metabolic sign. SARS-CoV2 complications and patient outcomes are connected with the blood glucose level . An essential characteristic of these conditions is poor glycemic control, which leads to inappropriate chemical reactions and glycated proteins producing the inflammatory response, resulting in the cytokine storm associated with COVID-19 morbidity and mortality . The well-balanced glycemic control is a tool for successfully managing COVID-19 infection, particularly challenging .
Furthermore, the post-COVID-19 syndrome has also emerged as a sequela in COVID-19 survivors, increasing the risk of deadly complications and further burdening the health care system. In SARS-Cov-2 infection, patients with hyperglycemia could be considered for a more intensive prophylactic hyperglycemic regimen . Metabolic disorders are found to be accompanied by vascular active peptides imbalance. The high NO ions levels in DM patients with the increased glucose levels were detected in serum, which might be responsible for the activation of endothelial cells to enhance NO levels .
The modified ACE expression represents the imbalance in RAS leading to the bradykinin receptors activation [40, 44]. The atypical pattern of the RAS is predicted to elevate bradykinin levels in multiple tissues and systems, resulting in vascular dilation, permeability, and hypotension. The well-known bradykinin-driven outcomes explain most of the symptoms observed in COVID-19  and the critical role of glucocorticoids in the acute and chronic management of inflammatory disease, independent of any effect of RAS .
The role of ACE inhibitors in the initiation of SARS-CoV2 dependent vascular complications remains unknown. Their application reduces the ACE activity in AH patients . But at the same time, the decrease in nitric ions level is shown in the investigation may be a sign of the ACE inhibitor's anti-inflammatory action . Found data verified the protective effect of ACE inhibitors on the outcome of COVID-19 patients.
The study revealed an increase in the activity of α1-PI, trypsin- and elastase-like proteinases in the blood plasma of patients with community-acquired pneumonia, especially pronounced during infection with SARS-C0V2. The data obtained are probably associated with the specific effect of the virus on the activation of proteolytic enzymes [13, 17], including due to molecular mimicry of viral proteins with proteinase furin on the α-subunit of the human epithelial sodium channel .
Elastase-like proteinases activity is associated with the development of nonspecific inflammation and lung parenchyma damage . The increase in elastase activity is insignificant; in the case of association with DM, it reaches its maximum values, exceeding the control group by 3.4 times.
Trypsin-like proteinases include trypsin, kallikrein, renin, thrombin, plasmin, complement system . An increase in the trypsin-like proteinase activity is associated with the RAS induction hemostasis imbalance, typical for SARS-CoV2 infection . At the same time, comorbidities are also accompanied by proteolysis hyperactivation. It is the reason for the COVID-19 adverse course in older people with comorbidities .
SARS-CoV2 acquired pneumonia is associated with the membrane trypsin-like proteinases induction and plasma proteolytic systems activation . Extracellular proteinases, TMPRSS2, and furin can also participate in the coronavirus spike protein priming . An increase in the neutrophil elastase and trypsin-like proteinase activity was found in SARS-CoV2 patients [13, 44]. The trypsin-like proteinase and neutrophil elastase activation occurs in the early stages of COVID-19. At the same time, neutrophil elastase activity was equally high in ARDS patients and patients with adverse outcomes. Thus, the inflammation's high rate is accompanied by an increase in the elastase and trypsin-like proteases activity. It is evidence of the blood plasma proteolysis implementation
Proteinase-activated receptors belong to the subfamily of seven-transmembrane receptors associated with G-protein are of great importance in down-streaming the proteinases action . Platelets express PAR4, which triggers platelet activation and participates in signaling and modulating cellular responses [46, 48, 49].
Serine, trypsin-like proteinases (thrombin, trypsin) activate PARs receptors present on the membranes of many cells: platelets, monocytes, macrophages, neutrophils, endothelial cells, which promote the activation of these cells .
The activation of thrombus inflammation is facilitated by neutrophil elastase, which is involved in forming NET (Neutrophil extracellular traps) [15, 50]. Indeed, our studies revealed an increase in elastase activity at the early stages of community-acquired pneumonia in COVID-19.
Community-acquired pneumonia is associated with the development of ARDS, and a decrease in pO2 most clearly shows the pathogenetic patterns of the disease. An increase in PAR4 content is probably an early sign of ARDS before the coagulopathy . It is logical to assume that the rise in PAR4 reflects the initial stages of thrombus inflammation in the lung tissue. Hypercoagulation leads to DIC syndrome (Disseminated intravascular coagulation) , stroke, and heart failure [52, 53].
The increase in PAR4 content may be due to the action of multiple stimuli related to thrombus inflammation, including angiotensin II, thrombin, trypsin-like proteinases, high glucose levels, and oxidative stress [46, 54, 55].
The PAR4 level decrease observed during hospitalization could be associated with the unfavorable course of COVID-19: patients with low PAR-4 levels had a negative clinical picture during hospitalization and were prescribed glucocorticoids. A low PAR-4 level at the early stages of COVID-19 indicates the development of severe infection. Indeed, in patients with low PAR-4 levels, an unfavorable outcome was recorded during hospitalization. It manifested at 2–3 weeks of hospitalization. A decrease in PAR4 content may be associated with the receptor–proteinase complex .
A comorbid pathology associated with initially overactive proteolysis probably causes an increase in the body's susceptibility to the SARS-CoV2 virus. Patients with low PAR4 levels had high trypsin-like proteinases and neutrophil elastase activity due to prolonged inflammation. Subsequently, the progression of the disease, the ARDS severity, and the multiorgan lesions manifestation led to the DIC syndrome and death.
The rise in neuropilin level was found in patients with community-acquired pneumonia. It is known that neuropilin is a gateway for the virus to disseminate throughout the body [25, 56, 57].
Moin A. S. M. et al. (2021) has revealed a relationship between neuropilin and glucose levels in DM patients . The obtained results may show the signs of nervous system damage in COVID-19, specifically for recovery from the infection without the concomitant metabolic disorders, mainly DM. Similar patterns are shown in single works.
A neuropilin decrease was correlated with the infection severity and adverse outcome. Compensated DM favorably affects the outcome of the disease , contributing to a decrease in mortality from concomitant complications. The patients without previously diagnosed metabolic disorders provide unique management. There is an association between the SARS-CoV2-associated hyperglycemia and the neuropilin level. Previous studies by Rizza S. et al. (2021), and Singh AK et al. (2020) showed the role of hyperglycemia in multiorgan lesions [58 59].
COVID-19 is a disease being induced by the increased virus transmission and infection rates due to the comprehensive expression of the main infection-related ACE2, TMPRSS2, and CTSB/L human genes in tissues of the respiratory and gastrointestinal tract, as well as by host- and probably aggressive inflammation and (due to broad organotropism of SARS-CoV-2) collateral tissue damage and systemic failure [Stehura AV, Sirchak YS, 2021]. The increase in ACE activity in COVID-19 patients with signs of heart damage was found.
Gastrointestinal manifestations such as diarrhea, vomiting, and abdominal pain are reported in many affected individuals. They may be due to the SARS-CoV-2 tropism for the peptidase angiotensin receptor 2 . Similarly, hepatic impairment patients co-infected with SARS-CoV-2 exhibited overexpression of ACE2 receptors and cytokine storm overwhelming, worsening the hepatic impairment and increasing the mortality rate .
Recently, another receptor, NRP-1, has been reported to amplify the viral infection. NRP-1 is expressed in nonparenchymal liver cells. It plays a significant role in the pathogenesis of COVID-19-induced intestinal lesions and enhances the systemic inflammatory responses . It has been observed that SARS-CoV-2 infection promotes liver injury through several pathways that may be influenced by the previous pathological status of the patient and liver expression of NRP-1 . The elevated neuropilin level was found in patients with severe inflammatory reactions with intestinal lesions. The adipose hormone increase revealed in the gastrointestinal failure, indicating the rate of inflammation. The rise in NO derivatives level, hyperactivation of proteolysis, and α1-PI activity is also seen.
The RAS imbalance results in nitrates increasing due to SARS-CoV2 induced biochemical effects. Its toxic effect on absorptive and secretive functions of the intestinal mucosa is well-known . It can signify a more severe systemic pro-inflammatory process with adipose tissue involvement. The summarise in biochemical mechanisms of SARS-CoV2 infection, role in the liver damage and intestinal lesions is shown in Fig. 1.