key: cord-0998451-sn8v26bz
authors: Wang, Stephani C.; Wang, Yu-Feng
title: Cardiovascular protective properties of oxytocin against COVID-19
date: 2021-01-26
journal: Life Sci
DOI: 10.1016/j.lfs.2021.119130
sha: 66a3d93165064045edbd5b324f4e42ff718a56a1
doc_id: 998451
cord_uid: sn8v26bz

SARS-CoV-2 infection or COVID-19 has become a worldwide pandemic; however, effective treatment for COVID-19 remains to be established. Along with acute respiratory distress syndrome (ARDS), new and old cardiovascular injuries are important causes of significant morbidity and mortality in COVID-19. Exploring new approaches managing cardiovascular complications is essential in controlling the disease progression and preventing long-term complications. Oxytocin (OXT), an immune-regulating neuropeptide, has recently emerged as a strong candidate for treatment and prevention of COVID-19 pandemic. OXT carries special functions in immunologic defense, homeostasis and surveillance. It suppresses neutrophil infiltration and inflammatory cytokine release, activates T-lymphocytes, and antagonizes negative effects of angiotensin II and other key pathological events of COVID-19. Additionally, OXT can promote γ-interferon expression, which inhibits cathepsin L and raises superoxide dismutase expression, to reduce heparin and heparan sulphate fragmentation. Through these mechanisms, OXT can block viral invasion, suppress cytokine storm, reverse lymphocytopenia, and prevent progression to ARDS and multiple organ failures. Importantly, besides prevention of metabolic disorders associated with atherosclerosis and diabetes mellitus, OXT can protect the heart and vasculature through suppressing hypertension, brain-heart syndrome, and social stress, and promoting regeneration of injured cardiomyocytes. Unlike other therapeutic agents, exogenous OXT can be used safely without the side-effects seen in remdesivir and corticosteroid. Importantly, OXT can be mobilized endogenously to prevent pathogenesis of COVID-19. This article summarizes our current understandings of cardiovascular pathogenesis caused by COVID-19, explores the protective potentials of OXT against COVID-19-associated cardiovascular diseases, and discusses challenges in applying OXT in treatment and prevention of COVID-19. CHEMICAL COMPOUNDS: Angiotensin-converting enzyme 2 (ACE2); atrial natriuretic peptide (ANP); cathepsin L; heparan sulphate proteoglycans (HSPGs); interferons; interleukin; oxytocin; superoxide dismutase; transmembrane serine protease Isoform 2 (TMPRSS2).

intervention and increased protein leakage from blood vessels, venous thromboembolism and shock [19] . The same importance applies to lymphocytopenia. For example, thymosin α1 supplement significantly reduces mortality of severe COVID-19 patients with the counts of CD8+ and CD4+ T cells in circulation lower than 400/µL and 650/µL, respectively. Thymosin α1 reverses T cell exhaustion and improves immune reconstitution by promoting thymus output during SARS-CoV-2 infection [20] . Thus, suppressing sustained release of cytokines and inflammatory response, and promoting Tlymphocyte functions are the essential therapeutic strategy to treat COVID-19 patients.

converting enzyme 2 (ACE2), transmembrane serine protease isoform 2 (TMPRSS2), lysosomal endopeptidase cathepsin L, and membrane bound heparan sulphate proteoglycans (HSPGs) and others [21] . As the receptor for SARS-CoV-2,ACE2 is present on the surface of lung alveolar epithelial cells, enterocytes of the small intestine, renal tubules, heart, arterial and venous endothelial cells, arterial smooth muscle cells, cerebral neurons and immune monocytes/macrophages [22; 23] . Spike proteins give and diabetes (9.2%) [13] . Patients with pre-existing conditions may face a greater risk of developing into the severe condition. Thus, old and new CV complications are worthy of special attention in COVID-19 patients.

In the dissemination of SARS-CoV-2 from the lung to multiple organs, endothelial dysfunction of the CV system is a common phenomenon. After infecting respiratory epithelial cells, SARS-CoV-2 gets into the circulation through endothelial cells of blood vessels in the lung and then enters tissues through the endothelial cells in capillaries again.

COVID-19 patients exhibit abnormalities in the vascular endothelium, which alter the blood flow, and evoke platelet function abnormalities and hyper-viscosity [32] .The endothelial dysfunction and damage cause release of procoagulant components, which together with hypoxia, immune reactions and hypercoagulability contributes to thrombogenesis [33] . Thus, endothelium is a critical barrier in COVID-19 transmission and dissemination.

CV injuries from viral infection are also mediated by ACE2 and cathepsin L [34] . In adult human heart, pericytes with high-expression of ACE2 serve as target cardiac cells for SARS-CoV-2. Infection in pericytes results in dysfunction of capillary endothelial cells and microvascular dysfunction. Patients with heart failure showed increased ACE2 expression at both mRNA and protein levels [35] .Among patients with diabetes and CV disease, the expression levels of TMPRSS2 are elevated significantly in comparison to J o u r n a l P r e -p r o o f Journal Pre-proof healthy individuals. Additionally, expression of viral entry-related genes is increased in the settings of hypertension across target organ systems [21] . Thus, if infected by the virus, these patients may have higher risk of CV complications and progression to critically-ill condition.

The etiology of CV injuries seems to be multifactorial including direct viral myocardial damage, hypoxia, hypoperfusion, enhanced inflammatory state, ACE2 downregulation, drug toxicity, endogenous catecholamine adrenergic status and others [36] .

The subsequent virus-mediated myocardial injury is closely related to inflammatory hyperactivity. For example, cardiac injury is significantly associated with inflammation biomarkers such as IL-6, C-reactive protein, hyperferritinemia, and leukocytosis along with elevated troponin I levels [31] . Direct cardiac injury following viral entry through ACE2 receptors is closely associated with cytokine storm [37] . In SARS-CoV-2 infected human, pluripotent stem cell-derived cardiomyocytes, double-stranded viral RNA and viral spike protein expressions are detected in intracellular space. In addition, viral spike protein and particles are present in living human heart slices after infection with SARS-CoV-2, which induces cytotoxic and proapoptotic reaction and abolish cardiomyocyte activities. One of the currently used treatments, remdesivir has been shown to inhibit viral infection of cardiomyocytes [34; 38] .

Further study also reveals that lung pathology can also cause CV malfunctions.

Clinical and experimental observations have shown that loss of ACE2 function aggravates pulmonary hypertension while restoring ACE2 function exerts protection on cardiopulmonary circulation. In addition, SARS-CoV-2 tropism and its interaction with the renin-angiotensin-aldosterone system (RAAS) system, through ACE2 receptor, may J o u r n a l P r e -p r o o f enhance inflammation response and cardiac aggression [31] .SARS-CoV-2 infection can lead to right heart dysfunction by inducing pulmonary hypertension, pulmonary embolism, and ARDS.

OXT, a nonapeptide synthesized in hypothalamic magnocellular neuroendocrine cells in the supraoptic and paraventricular nuclei (SON and PVN), is a well-known humoral factor regulating parturition and lactation [6; 39] . In the brain, OXT terminals are found on large intracerebral arteries [40] . OXT-containing neural fibers are present in piaarachnoids, blood vessels at the base of the brain and over the dorsal surface [41] . Thus, OXT can regulate cerebral blood flow directly. Moreover, OXT and OXT receptor (OTR) are identified in the pulmonary artery, vena cava and aorta of rats, dogs and sheep [42] as well as cardiac cells in rats [43] and endothelial cells of human umbilical vein endothelial cells [44] . They allow OXT to regulate CV activity at peripheral sites as well.

OXT can modulate CV activity including the development of cardiomyocytes, ionotropic and chronotropic effects, dual role in cardiac output, endocrine activity (i.e. atrial natriuretic peptide, ANP, secretion) and direct cardioprotection [7] .

In general, OXT exerts negative chronotropic and ionotropic effects on cardiac activity. OXT can reduce heart rate and cardiac contractility by activating intrinsic cardiac cholinergic neurons of the vagus and promoting nitric oxide (NO) production. This is because atropine and NO synthase inhibitor, L-NAME, can significantly inhibit J o u r n a l P r e -p r o o f this OXT effect [45] . Consistently, in OXT knockout mice, there were mild hypotension, higher sympathetic tone and higher heart rate [46], indicating activation of sympathetic outflow. Thus, OXT participates in the maintenance of tonic blood pressure and suppression of sympathetic reserve. Notably, direct inhibitory OXT effects identified in animal studies are largely pharmacological. At higher concentrations, OXT can directly reduce left ventricle pressure and heart rate in isolated rat hearts and decrease mean artery pressure in rats, which could involve the action of ANP [47] .

OXT can protect the CV system from social stress damages or the brain-heart syndrome via neural and endocrine approaches. Social stress is important etiology of CV malfunctions because it can disrupt normal behavior, neuroendocrine, and autonomic responses. By facilitating positive social interactions, suppressing sympathetic outflow and reducing fear and anxiety, OXT can counteract the deleterious effects of social stress and its associated unhealthy life-style, hypertension, and coronary artery diseases Another approach for OXT protection is its influencing the secretion of many cytokines [50; 51]. For example, OXT infusion dose-dependently increases plasma ANP concentration as much as 4-fold after 20 min. ANP produced in the right atrium can prevent reperfusion arrhythmia and maintain ATP production in ischemic tissue while facilitating Na + excretion to reduce after-load and blood pressure [52] . Moreover, OXT can suppress the activity of hypothalamic-pituitary-adrenocortical axis [53] , and then reduce the release of stress hormone. Through these approaches, OXT can reduce heart rate and blood pressure while increasing the reserve of cardiac output, thereby exerting CV protective effects. [62] . In the posterior pituitary, OXT-containing axonal terminals express vascular endothelial growth factor A that can cause active proliferation of endothelial cells [63] . By protecting endothelial cells in blood vessels and stabilizing anticoagulant heparan [64] , OXT could reduce the formation of thromboembolism and atherosclerosis while blocking pathogen invasion. Figure 1 summarizes the CV protective effects and potential involvement of OXT in COVID-19-associated CV diseases.

The OXT-secreting system is considered as the higher neuroendocrine regulation center of the immune system [50; 51] and key protective factor of CV system. Interruption of this system by COVID-19 partially accounts for the CV complications while reviving the OXT-secreting system or supplying OXT becomes a feasible strategy of inhibiting the pathogenesis of CV manifestations in COVID-19.

The pathological changes in CV system of COVID-19 patients could result from dysfunction of the OXT-secreting system. In epidemiology, the decline in OXT and OTR with aging is likely responsible for the increased incidence of CV diseases since weakened OTR signaling can accelerate inflammatory and oxidative injuries, particularly J o u r n a l P r e -p r o o f among menopausal women [53 ; 65] . In aged man, OXT secretion is also reduced, which is in parallel with increased incidence of hypertension, coronary artery disease, diabetes and cerebrovascular diseases. These diseases are also the common comorbidities that increase susceptibility to COVID-19 diseases [11] . Consistently, plasma OXT level experiences a 3-fold decline in aged mice compared with young, and this decline is accompanied by similar decrease in OTR levels in muscle stem cells [66] . By contrast, exogenous estrogen application can increase OXT secretion, OTR mRNA expression in mouse brain [67] , and intracardiac OTR signaling [68] , which simulates the physiology of young women who are less susceptible than menopausal women to COVID-19. In addition, melatonin, a pineal hormone that has remarkable anti-inflammatory effects and can antagonize various viral infections including COVID-19 [69] , can also regulate OXT release [70] . Thus, the susceptibility to COVID-19 is highly correlated with the activity of the OXT-secreting system.

In COVID-19 patients, there is also evidence indicating involvement of the hypothalamic-pituitary system. In two SARS-CoV-2 infected patients, the mammillary bodies and hypothalamus carried T2-hyperintensity, the pituitary gland was enlarged, and the upper pituitary stalk seemed globular in sagittal fluid-attenuated inversion recovery [71] . Since the mammillary bodies can function as the upstream center of OXT neuronal activity, particularly its release in a pulsatile pattern [72], viral infection of the mammillary bodies unavoidably changes the downstream OXT neuronal activity and OXT secretion. In COVID-19 patients, many brain areas innervated by olfactory bulbs including the hypothalamus showed hypometabolism in 18 F-FDG positron emission tomography scans [16], suggesting low olfaction-associated hypothalamic J o u r n a l P r e -p r o o f neuroendocrine activity. It is also reported that activation of ACE2 in the PVN increases neuronal NO synthase and NO production, which can increase sympatho-inhibitory GABA activity and decrease sympatho-excitatory AT II signaling and glutamate activity [73] . ACE2 can reduce oxidative stress and cyclooxygenase-mediated neuroinflammation, improve antioxidant and NO signaling, and attenuate the development of neurogenic hypertension [74] . Studies on pathological changes in the hypothalamus of SARS-CoVassociated diseases also support the involvement of the hypothalamic neuroendocrine system in COVID-19. For example, in autopsies of 8 SARS patients, SARS-CoV was identified in the cytoplasm of numerous neurons in the hypothalamus and cortex [75] . In post-mortem tissues from HIV patients, OXT immunoreactivity in hypothalamic neurons decreased significantly [76] . Since these viruses use the same mechanisms of cellular infection and disruption as SARS-CoV-2, disruption of endogenous OXT production could be one etiology leading to the progression of COVID-19. It is likely that SARS-CoV-2 enters the brain from the nose to the olfactory bulb followed by viral infection of neurons in hypothalamus via the olfactory nerve [16] . The olfactory bulb involvement is supported by the high rates of anosmia or hyposmia in patients with COVID-19 [81] and by neural connections between the olfactory bulb and SON [82] . Alternatively, SARS-CoV-2 in the blood can enter the hypothalamus and pituitary through fenestrated capillaries of blood-brain barrier around the third ventricle and pituitary [83] . Direct evaluation of plasma OXT levels and examination of hypothalamic histology of COVID-19 patients are needed to further clarify this association.

Cytokine storm and lymphocytopenia are two major features of immunological disorders among COVID-19 patients. OXT has the potential to suppress cytokine storm. Diffuse pneumocytes and alveolar damage with pulmonary edema, proteinaceous exudate, inflammatory cell infiltrates, and release of pro-inflammatory cytokines can lead to cytokine storm [84] . This process can be suppressed by OXT administration. As shown in J o u r n a l P r e -p r o o f animal studies, exogenous OXT can decrease levels of IL-1β, IL-6, IL-18, and myeloperoxidase as well as incidence of acute lung injury in mice induced by lipopolysaccharide, an endotoxin [85] . OXT can downregulate neutrophil chemotactic molecules and myocardial neutrophil infiltration, and prevent myocardial injury by reducing inflammatory reaction, reactive oxygen species, and apoptosis caused by neutrophils [86] . In both smooth muscle and vascular endothelial cells, OXT can inhibit oxidative stress and pro-inflammatory cytokine release [87; 88] , thereby attenuating the cytokine storm and inflammation.

Additionally, OXT has the potential to block SARS-CoV-2 infection of cells and reduce SARS-CoV-2 loads. OXT can induce γ-interferon expression as shown in mouse spleen cell cultures [89] . Interferons can reduce viral infections by producing γinterferon-inducible lysosomal thiol reductase that restricts the entry of selected enveloped RNA viruses via disrupting cathepsin L metabolism [90] . This potential of OXT is supported by the fact that at 24-hours following weaning of suckling when OXT levels reduce, cathepsin L and cell apoptosis increase dramatically in mouse mammary glands [91] . Another potential approach of OXT blocking SARS-CoV-2 infection is blocking HSPGs-mediated viral infection. -OXT can induce the expression of extracellular superoxide dismutase [92] , an antioxidant enzyme that has been shown to protect tissues from reactive oxygen species-induced heparin and heparan sulphate fragments, and thus the subsequent neutrophil chemotaxis [64] . Importantly, heparin and heparan sulphate can antagonize the binding of SARS-CoV-2 to HSPGs and block their cellular internalization [93] . Through these approaches, OXT has the potential to prevent SARS-CoV-2 entry and disruption of cells.

J o u r n a l P r e -p r o o f OXT can also reduce viral load by reversing lymphocytopenia. As reported, OXT acts on OTR in the thymus to promote the differentiation of T-lymphocytes [94] . OXT elicits a functional intracellular [Ca 2+ ] response in T-lymphocytes to activate resident Tlymphocytes [95] . In women infected with HIV that has spike proteins highly homologous to COVID-19, high-level of OXT was associated with a positive correlation between stress and CD4 cell counts [96] . In a recent study, OXT was found to be more effective than hydroxychloroquine or lopinavir in modulating inflammation, and enhancing T-lymphocyte activation [97] . These findings suggest that OXT can prevent or alleviate lymphocytopenia in COVID-19 patients and thus reduce SARS-CoV-2 load, making OXT an ideal candidate for clinical trial for treatment of COVID-19.

Besides immunological modulation, OXT may reduce CV injury from COVID-19 by increasing cellular integrity, particularly endothelium. First, OXT can prevent ACE2 loss by increasing T-lymphocytes that can in turn reduce SARS-CoV-2 viral load and cellular injuries [98] . Second, OXT maintains cell integrity by reducing neutrophil-mediated inflammatory injury and cardiac apoptosis [99] . Third, OXT may protect endothelial cells by increasing vascular endothelial growth factor [57] and promoting angiogenesis [44] . Fourth, OXT antagonizes the adverse effect of AT II on the CV system by increasing ANP production [7] . ANP can reduce renin and thus AT II activity in the RAAS thus reducing damages in endothelial, pulmonary, and CV systems from COVID- [102] . Lastly, OXT can inhibit carbonic anhydrase activity that is associated with hypoxic pulmonary vasoconstriction, pulmonary hypertension right ventricle hypertrophy and fibrosis among COVID-19 patients [103] .

While direct evidence on OXT modulation of ACE2 and AT II remains to be collected, OXT can be used to antagonize AT II effects in COVID-19 patients.

CV system is a major target of COVID-19 that causes myocardial infarction, fulminant myocarditis, heart failure, arrhythmias, venous thromboembolism, and cardiomyopathies [14; 31; 104; 105] . OXT exerts cardioprotective functions by reducing inflammation and cardiac fibrosis, improving left ventricular function, enhancing prosurvival kinases, elevating parasympathetic tone, reducing the infarct size, and protecting the heart from myocardial injury [7] . For example, OXT pre-treatment inhibits the degranulation of cardiac mast cells induced by ischemia and reperfusion injury, and down-regulates the expression of inflammatory factors [106] . OXT also functions as an anti-arrhythmic agent. For example, acute myocardial ischemia is accompanied by a rapid increase in electrical instability and often fatal ventricular arrhythmias. OXT can cause a significant and biphasic dose-dependent reduction in ectopic heart activity and arrhythmia score [107] . Intranasal application of OXT significantly reduces brain infarction and maintains the integrity of the blood-brain barrier in mice [108] and rats Metabolic and immunological disorders are essential etiologies underlying obesity, atherosclerosis and the associated diseases, such as hypertension, coronary artery disease and ischemic stroke [112] . OXT does not only carry anti-inflammatory effects as stated above but also reduces hyperlipidemia, an essential metabolic disorder for obesity and atherosclerosis. As reported, serum OXT levels were low in obese person [113] ; OXT-or OTR-deficient mice developed late-onset obesity [114] . In response to subcutaneous injection of OXT, cholesterol levels decreased in rats [115] . Chronic OXT application also reduced weight gain in diet-induced obese mice and rats; chronic subcutaneous or J o u r n a l P r e -p r o o f intranasal OXT treatment was sufficient to elicit body weight loss in obese humans [116] .

Thus, OXT may reduce individual susceptibility to COVID-19 by suppressing obesity, atherosclerosis and its complications.

OXT has the potential to inhibit the development of hypertension. In hypertensive rats, OXT and OXT mRNA expressions are reduced in the hypothalamus whereas, OXT injected subcutaneously or intracerebroventricularly for 5 days can significantly decrease blood pressure in rats [117] . Centrally released OXT can significantly reduce blood pressure and heart rate to antagonize acute stress-induced CV responses [118] . Moreover, chronic activation of OXT neurons restores the release of OXT from PVN neural fibers in the dorsal motor nucleus of the vagus, and prevents chronic intermittent hypoxia-evoked hypertension [119] . Based on these findings, we believe that OXT can exert antihypertensive effects through both central and peripheral approaches.

Population with diabetes mellitus has high prevalence of CV diseases [120] and high susceptibility to COVID-19. In patients with type 2 diabetes mellitus, serum OXT levels are relatively low [113] . In a mouse model of type 2 diabetes mellitus, OXT, OTRs, ANP, and endothelial NO synthase gene expressions in the heart are low [121] . In fasting men, intranasal OXT application can attenuate the peak excursion of plasma glucose [122] .

Mechanistically, OTR signaling attenuates the death of beta cells in pancreatic islets exposed to cytotoxic stresses [123] and increases beta-cell response to the glucose J o u r n a l P r e -p r o o f challenge [122] . Furthermore, OXT can promote glucose uptake in cultured cardiomyocytes from newborn and adult rats [124] , in myocardial cells during hypoxia [125] and in mesenchymal stem cells [126] . These facts indicate that OXT plays a significant role in the regulation of glucose metabolism and can prevent development and progression of diabetes mellitus. Thus, OXT could be used to reduce COVID-19 morbidity through glycemic control and stabilization.

Anxiety and panic are common responses in COVID-19 patients especially with ARDS [127] . OXT can reduce the expression of panic-related behaviors (e.g. fear and escape) by acting on the medial amygdala and the dorsal periaqueductal gray as previously reviewed [51] . OXT is positively associated with diminished stress among securely attached participants and can attenuate perception of stress due to adverse life events in old age [128] . In stroke, social pairing in adult mice enhances hypothalamic OXT gene expression and leads to smaller infarct size by reducing neuroinflammation and oxidative stress [112] . OXT can reduce stress-elicited neuroendocrine, autonomic, and behavioral responses [53], which can be used to prevent the brain-heart syndrome [129] . In addition, OXT also has anti-depressive effects [130] and may be used to relieve social isolationassociated depression in COVID-19 patients [48] . Thus, OXT/OTR signaling contributes to cardio-protection through diverse approaches in COVID-19.

In prevention and treatment of COVID-19, particularly the CV complications, OXT or OTR agonist is an ideal candidate for clinical trials. The following questions should be considered before its trials in management of COVID-19.

Further investigation is needed in order to clarify OXT and its potential role in prevention and treatment of hyperthrombotic state. Some observations suggest that OXT can promote platelet aggregation. For example, inducing labor by using OXT tends to increase platelet aggregation and decrease disaggregation [131] ; synthetic polyphosphate can inhibit OXT-induced platelet aggregation by reducing platelet Ca 2+ levels and inhibiting the thromboxane A2 signaling pathway [132] . Notably, OXT has different effects on ADP-induced platelet aggregation at different reproductive states. That is, the aggregation is potentiated at low (<200 nM) and inhibited at high (>400 nM) ADP concentrations in nonpregnant women; in pregnant women OXT does not or negligibly modulate ADP-induced platelet aggregation [133] . Since most of these observations are associated with labors and depending on the doses of OXT applied, the pro-coagulation effect of OXT may facilitate homeostasis during labors. In contrast, OXT generally protects endothelial cells from immunological injuries [110] , increases anticoagulant heparan sulphate stability, and reduces adhesion molecules [110] , and thus could reduce the formation of thrombosis. These facts support the possibility that OXT may reduce the pro-thrombotic state in non-pregnant COVID-19 patients. increased OXT release, which was inhibited by melatonin [134] , an agent having CV protective function. Acute myocardial infarction can increase brain release of OXT in the PVN which mediates sympatho-excitatory responses and the production of proinflammatory cytokines in rats [135] . Various stressors can provoke sudden CV effects and trigger the release of OXT in rats. However, administration of exogenous OXT on the ischemic-reperfused isolated heart of rats still reduced infarct size, levels of creatine kinase MB isoenzyme and lactate dehydrogenase in coronary effluent, and severity of ischemia and reperfusion injury [136] . As for the inhibition of OXT level by the CV protective melatonin [137] , this effect is likely due to dose-dependent effects of melatonin on OXT secretion [70] . Taken together, these findings support that OXT is critical in immunologic surveillance [50] and the increased OXT levels function as an compensatory reaction to the acute hypoxia injury.

Another question is whether cardiac-specific over-expression of OTR is beneficial to myocardial functions. In mice with cardiac-specific over-expression of OTR, the left ventricular function was reduced, end-diastolic volume was larger and high mortality along with cardiac fibrosis, atrial thrombus, and increased expression of pro-fibrogenic genes [138] . Interestingly, in rat dams separated from her pups, hypothalamic OXT secretion increased; however, plasma OXT levels were low. This is due to over-activation of OTR signaling causes post-excitation inhibition and a subsequent reduction of the J o u r n a l P r e -p r o o f secretory activity of OXT neurons [130, 139] . Thus, it is possible that over-expression or over-activation of OTR exerts an opposite effect of the physiological effect.

The third question is about the effect of OXT on renin secretion. In denervated kidney, direct infusion of OXT can significantly increase renin secretion from the kidneys in association with the activation of β-adrenoceptors [140] . This effect is likely due to that the denervation of sympathetic nerve increased the expression of βadrenoceptors or its sensitivity to adrenergic agonist, which amplifies a weaker OXT effects on renin secretion without the antagonism of secondary ANP release from the atrium and inhibition of sympathetic outflows from the PVN by OXT in vivo. As a whole, OXT increase during acute CV injuries can be viewed as a biomarker of cardiac stresses and the compensatory reaction of body defense system, but not an inducer of CV injuries.

OXT in the blood could differentially modulate CV activities, depending on the amount and pattern of its secretion from the posterior pituitary. This is because the effects of OXT on its targets are time-, dose-and pattern-dependent [141] . That is, longer and higher dose of OXT stimulation can cause inhibition of target cells following initial excitation [142; 143] ; OXT released in bolus can cause stronger response than the same amount of OXT in lower dose for longer time [144] . In the CV system, the same characteristics are also present. For example, in isolated hearts, 10 -7 M OXT caused 10% the pressor effect of high-dose OXT is actually mediated by vasopressin receptors [147] .

Under different conditions, expressions of OXT and OTR are also different [43] , which make OXT effects on CV system different following changes in CV activity, such as the effect of cardiac-specific over-expression of OTR in mice [138] .

In addition, the action of OXT is tissue-specific. In isolated dog carotid arteries, OXT causes vasoconstriction by acting on smooth muscle cells [148] and human basilar artery [41] . It is also reported that OXT in 10 -11 -10 -7 M levels causes relatively weaker contraction of basilar artery compared to vasopressin and has no effects on mesenteric arteries in rat [149] . Intramuscular injection of OXT decreases uterine blood flow during uterine contractions in puerperal dairy cows [150] , which occurs at postpartum day 2 but not day 5. Lastly, patterns of OXT actions are also important for its effect. For example, Pulsatile but not tonic secretion of OXT plays the role of anti-precancerous lesions of the mammary glands in rat dams [151] ; social desirability and milk transferred from the mother to the baby are largely dependent on OXT pulsatility [152] . Thus, in application of OXT, it is necessary to consider the location of target tissue-and organ-specific effect, the time-and dose-dependent effects as well as the patterns of application.

In management of COVID-19, many drugs have been considered, such as ACE blockers, anti-inflammatory drugs, antibodies against IL-1 and anti-IL-6, remdesevir, dexamethasone, hydroxychloroquine and vaccines [153] . In clinical studies, their J o u r n a l P r e -p r o o f efficacies are either under further evaluation or ineffective. For instance, COVID-19 patients' sera have only limited cross-neutralization [26] , suggesting that recovery from one infection might not protect against the other. In patients with COVID-19, the hypothalamic-pituitary-adrenocortical axis is likely inhibited as stated above, which makes corticosteroids critical for prevention of cytokine storm [154] ; however, it delays virus clearing but does not convincingly improve survival or reduce hospitalization duration and the use of mechanical ventilation [155] . Hydroxychloroquine previously used to treat COVID-19 is known to prolong the QT interval and can have a proarrhythmic propensity [36] . Right now it is not given to COVID-19 patients as it is considered to be ineffective [156; 157] . Lastly, COVID-19 vaccines have been developed extensively; however, their safety and efficacy profiles remain to be established. Notably, at 6 months after acute infection, COVID-19 survivors are troubled with fatigue, sleep difficulties, anxiety or depression and even severe impaired pulmonary diffusion capacities and abnormal finding on pulmonary imaging tests [158] . So far, there are currently no known specific, effective treatments for COVID-19. OXT, with broadspectrum anti-COVID-19 potential, is relatively safe compared to antiviral drugs and corticosteroids, and inexpensive relative to antiviral therapies [3; 111] , and thus is worthy of clinical trial to validate its efficiency.

In treatment of CV diseases, many approaches of applying OXT have been proposed [7] . These considerations are also viable for treating CV complications in COVID-19. In brief, OXT or its agonists can be used exogenously by intravenous infusion, intramuscular injection or intranasal application. OXT can be used in a continuous low dose to minimize potential CV disturbances, or in bolus to maximize the J o u r n a l P r e -p r o o f efficiency without desensitizing OTR. OXT can also be used in nasal approach to activate the OXT-secreting system. Special caution should be taken for pregnant women around labors, particularly for those who are allergic to OXT or have high basal AT II levels. As reported that acute systemic administration of low-dose OXT exerted a protective role; however, chronic subcutaneous administration of low-dose OXT (20 or 100 ng/Kg/h, for 28 days) can enforce AT II-induced hypertension, cardiac hypertrophy, and renal damage in rats although OXT itself does not have these effects [159] . Future laboratory study and clinical trial of OXT usage are critical in translating its therapeutic potentials into reality, not only for COVID-19 but its application may be extended to other future viral infections.

Besides the needs for treatment, prevention of COVID-19 is another irreplaceable potential of OXT. Human-to-human transmission via droplets and contaminated surfaces has been described, from both symptomatic and asymptomatic patients. Correspondingly, wearing mask and social distance have been adopted as common prevention measures.

While these measures are effective in reducing COVID-19 morbidity, they also raise concerns for massive social isolation and long-term psychological effects [160] that decrease immunological defense [50; 51] and thus can increase COVID-19 susceptibility.

It is known that social isolation can cause CV complications [161] while disrupting normal OXT secretion [162; 163; 164] . Importantly, application of OXT can alleviate social isolation-induced atherosclerosis and adipose tissue inflammation [165] . Currently, newly developed specific vaccines face the challenge of continued mutations inSARS-J o u r n a l P r e -p r o o f CoV-2 [166; 167] and complete social isolation is difficult to achieve, which leave majority of the population remaining in the risk of COVID-19. Thus, strengthening the basic immunologic function is a measure that universally fits our human society, particularly for aged population who have reduced immunologic function and OXT production [168] . For this purpose, mobilization of endogenous OXT can be an optimal approach to improve our resistance to COVID-19 by blocking SARS-CoV-2 entry, reducing viral load, or reducing pre-existing comorbidities.

OXT is a "social hormone" and can be elicited by many types of healthy behavior via increasing vagal inputs and by conditioned reflex, such as massage [169] , listening to music [170] , brief mindfulness session [171] , light therapy [134] , and physical exercise [172; 173] . Although the integrity of our human society can be disrupted by self-isolation and social distancing, mobilizing endogenous OXT functions can help us to rebuild it by giving individuals of high immunologic defense capacity and lower susceptibility to COVID-19 through simply mobilizing our inherent potentials. 

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Negative inotropic and chronotropic effects of oxytocin

The hypothalamic neuropeptide oxytocin is required for formation of the neurovascular interface of the pituitary

VEGFdependent and PDGF-dependent dynamic neurovascular reconstruction in the neurohypophysis of adult mice

Extracellular superoxide dismutase protects against matrix degradation of heparan sulfate in the lung

Oxytocinergic activity is linked to lower blood pressure and vascular resistance during stress in postmenopausal women on estrogen replacement

Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration

Effects of estrogen on oxytocin receptor messenger ribonucleic acid expression in the uterus, pituitary, and forebrain of the female rat

Cardiac oxytocin receptor blockade stimulates adverse cardiac remodeling in ovariectomized spontaneously hypertensive rats

Melatonin potentials against viral infections including COVID-19: Current evidence and new findings

The role of melatonin membrane receptors in melatonin-dependent oxytocin secretion from the rat hypothalamo-neurohypophysial system -an in vitro and in vivo approach

Lesions of hypothalamic mammillary body desynchronise milk-ejection bursts of rat bilateral supraoptic oxytocin neurones

Angiotensin-(1-7) in paraventricular nucleus modulates sympathetic activity and cardiac sympathetic afferent reflex in renovascular hypertensive rats

Brain-targeted angiotensin-converting enzyme 2 overexpression attenuates neurogenic hypertension by inhibiting cyclooxygenase-mediated inflammation

Multiple organ infection and the pathogenesis of SARS

Contributions of HIV infection in the hypothalamus and substance abuse/use to HPT dysregulation

Effect of serum total testosterone and its relationship with other laboratory parameters on the prognosis of coronavirus disease 2019 (COVID-19) in SARS-CoV-2 infected male patients: a cohort study

Thyroid Function Analysis in 50 Patients with COVID-19: A Retrospective Study

An Impaired Natriuretic Peptide Hormone System May Play a Role in COVID-19 Severity in Vulnerable Populations

Oxytocin response to controlled dietary sodium and angiotensin II among healthy individuals

Autonomic Brain Centers and Pathophysiology of COVID-19

Oxytocin Removes Estrous Female vs. Male Preference of Virgin Male Rats: Mediation of the Supraoptic Nucleus Via Olfactory Bulbs

Multiple Neuroinvasive Pathways in COVID-19

Protective effect of oxytocin on LPS-induced acute lung injury in mice

Oxytocin ameliorates the immediate myocardial injury in rat heart transplant through downregulation of neutrophil-dependent myocardial apoptosis

Oxytocin attenuates NADPH-dependent superoxide activity and IL-6 secretion in macrophages and vascular cells

Oxytocin administration attenuates atherosclerosis and inflammation in Watanabe Heritable Hyperlipidemic rabbits

Regulation of lymphokine production by arginine vasopressin and oxytocin: modulation of lymphocyte function by neurohypophyseal hormones

GILT restricts the cellular entry mediated by the envelope glycoproteins of SARS-CoV, Ebola virus and Lassa fever virus

Standardization and validation of an induced ovulation model system in buffalo cows: Characterization of gene expression changes in the periovulatory follicle

Vasoactive factors and growth factors alter vascular smooth muscle cell EC-SOD expression

Heparin-binding Peptides as Novel Therapies to Stop SARS-CoV-2 Cellular Entry and Infection

Ontogenesis and functional aspects of oxytocin and vasopressin gene expression in the thymus network

Expression and regulation of functional oxytocin receptors in bovine T lymphocytes

Stress buffering effects of oxytocin on HIV status in low-income ethnic minority women

Oxytocin's anti-inflammatory and proimmune functions in COVID-19: a transcriptomic signature-based approach

Immunopathology of SARS-CoV-2 Infection: Immune Cells and Mediators, Prognostic Factors, and Immune-Therapeutic Implications

Oxytocin ameliorates the immediate myocardial injury in heart transplant through down regulation of the neutrophil dependent myocardial apoptosis

Renal function after myocardial infarction and cardiac arrest in rats: role of ANP-induced albuminuria?

Oxytocin as feeding inhibitor: maintaining homeostasis in consummatory behavior

Sympathetic activation: a potential link between comorbidities and COVID-19

Acetazolamide, Nifedipine and Phosphodiesterase Inhibitors: Rationale for Their Utilization as Adjunctive Countermeasures in the Treatment of Coronavirus Disease

Overcoming Barriers: The Endothelium As a Linchpin of Coronavirus Disease

COVID-19 pandemic and cardiovascular disease: where do we stand? Minerva cardioangiologica

Oxytocin ameliorates ischemia/reperfusion-induced injury by inhibiting mast cell degranulation and inflammation in the rat heart

Effect of different doses of oxytocin on cardiac electrophysiology and arrhythmias induced by ischemia

Oxytocin Reduces Brain Injury and Maintains Blood-Brain Barrier Integrity After Ischemic Stroke in Mice

Neuroprotective Effects of Oxytocin Hormone after an Experimental Stroke Model and the Possible Role of Calpain-1

Oxytocin inhibits ox-LDL-induced adhesion of monocytic THP-1 cells to human brain microvascular endothelial cells

The epidemiology, diagnosis and treatment of COVID-19

Pathological basis of cardiac arrhythmias: vicious cycle of immune-metabolic dysregulation

Decreased circulating levels of oxytocin in obesity and newly diagnosed type 2 diabetic patients

Oxytocin receptor-deficient mice developed late-onset obesity

Modification of fat and carbohydrate metabolism by neurohypophyseal hormones. III. Effect of oxytocin on non-esterified fatty acid, glucose, triglyceride and cholesterol levels in rat serum

Translational and therapeutic potential of oxytocin as an anti-obesity strategy: Insights from rodents, nonhuman primates and humans

Postnatal oxytocin treatment of spontaneously hypertensive male rats decreases blood pressure and body weight in adulthood

Central oxytocin modulation of acute stress-induced cardiovascular responses after myocardial infarction in the rat

Oxytocin neuron activation prevents hypertension that occurs with chronic intermittent hypoxia/hypercapnia in rats

Diabetes Mellitus and Heart Failure

Downregulation of oxytocin and natriuretic peptides in diabetes: possible implications in cardiomyopathy

Oxytocin Improves beta-Cell Responsivity and Glucose Tolerance in Healthy Men

Oxytocin increases glucose uptake in neonatal rat cardiomyocytes

The conserved phosphoinositide 3-kinase pathway determines heart size in mice

Preconditioning of stem cells by oxytocin to improve their therapeutic potential

Panic and pandemic: Narrative review of the literature on the links and risks of panic disorder as a consequence of the SARS-CoV-2 pandemic

Oxytocininduced coping with stressful life events in old age depends on attachment: findings from the cross-sectional KORA Age study

The Brain-Heart Connection in Takotsubo Syndrome: The Central Nervous System, Sympathetic Nervous System, and Catecholamine Overload

Key Roles of Cyclooxygenase 2-Protein Kinase A-Hyperpolarization-activated Cyclic Nucleotide-gated Channel 3 Pathway in the Regulation of Oxytocin Neuronal Activity in Lactating Rats with Intermittent Pup-Deprivation

Studies on platelet function during different modes of administration of PgF2alpha in obstetrics and gynecology

Synthetic polyphosphate inhibits endogenous coagulation and platelet aggregation in vitro

Effects of oxytocin and prostaglandin F(2alpha) (enzaprost) on platelet aggregation

Function of the hypothalamo-neurohypophysial system in rats with myocardial infarction is modified by melatonin

Microglial P2X(7) receptor in the hypothalamic paraventricular nuclei contributes to sympathoexcitatory responses in acute myocardial infarction rat

The effect of acute stress exposure on ischemia and reperfusion injury in rat heart: role of oxytocin

Melatonin is a potential adjuvant to improve clinical outcomes in individuals with obesity and diabetes with coexistence of Covid-19

Cardiac-Specific Overexpression of Oxytocin Receptor Leads to Cardiomyopathy in Mice

Involvement of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel 3 in Oxytocin Neuronal Activity in Lactating Rats With Pup Deprivation

Oxytocininduced renin secretion by denervated kidney in anaesthetized rat

Neural mechanisms underlying the milk ejection burst and reflex

Autofeedback effects of progressively rising oxytocin concentrations on supraoptic oxytocin neuronal activity in slices from lactating rats

Dominant role of betagamma subunits of G-proteins in oxytocin-evoked burst firing

Milk ejection and its control

Irisin and Oxytocin as Predictors of Metabolic Parameters in Obese Children

Oxytocin by intranasal and intravenous routes reaches the cerebrospinal fluid in rhesus macaques: determination using a novel oxytocin assay

The cardiovascular effects of oxytocin in conscious male rats

Effects of peptides and nonpeptides on isolated arterial smooth muscles: role of endothelium

Regional differences in the contractile activity of neuropeptide Y, endothelin, oxytocin and vasopressin: comparison with non-peptidergic constrictors. An in vitro study in the basilar and mesenteric arteries of the rat

Effects of exogenous oxytocin on uterine blood flow in puerperal dairy cows: the impact of days after parturition and retained fetal membranes

Pulsatile but not Tonic Secretion of Oxytocin Plays the Role of Anti-Precancerous Lesions of the Mammary Glands in Rat Dams Separated from the Pups during Lactation

Uvnas-Moberg K (1998) Oxytocin, prolactin, milk production and their relationship with personality traits in women after vaginal delivery or Cesarean section

Coronavirus COV-19/SARS-CoV-2 affects women less than men: clinical response to viral infection

What we have to know about corticosteroids use during Sars-Cov-2 infection

Impact of corticosteroid therapy on outcomes of persons with SARS-CoV-2, SARS-CoV, or MERS-CoV infection: a systematic review and meta-analysis

Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19

Effect of Hydroxychloroquine on Clinical Status at 14 Days in Hospitalized Patients With COVID-19: A Randomized Clinical Trial

Prolonged Subcutaneous Administration of Oxytocin Accelerates Angiotensin II-Induced Hypertension and Renal Damage in Male Rats

Multidisciplinary research priorities for the COVID-19 pandemic: a call for action for mental health science

Social isolation and cardiovascular disease: an atherosclerotic pathway?

Social isolation rearing-induced anxiety and response to agomelatine in male and female rats: Role of corticosterone, oxytocin, and vasopressin

Effects of postweaning social isolation on social behaviors and oxytocinergic activity in male and female rats

Relation of oxytocin to psychological stress responses and hypothalamic-pituitary-adrenocortical axis activity in older women

Oxytocin attenuates atherosclerosis and adipose tissue inflammation in socially isolated ApoE-/-mice

Human SARS CoV-2 spike protein mutations

Acharya P (2020) D614G Mutation Alters SARS-CoV-2 Spike Conformation and Enhances Protease Cleavage at the S1/S2 Junction

Adversity impacting on oxytocin and behaviour: timing matters

Potential combination of back massage therapy and acupressure as complementary therapy in postpartum women for the increase in the hormone oxytocin

Soothing music can increase oxytocin levels during bed rest after openheart surgery: a randomised control trial

Brief mindfulness session improves mood and increases salivary oxytocin in psychology students

Differential effects of vasopressinergic and oxytocinergic preautonomic neurons on circulatory control: reflex mechanisms and changes during exercise

Effect of exercise training on cardiac oxytocin and natriuretic peptide systems in ovariectomized rats