While COVID-19 primarily affects the lungs, it also affects other organs, the heart in particular. 2021;290:43743. In addition, COVID-19 is an important risk factor for developing acute myocardial infarction [29]. 2021;6:eabh2259. Luca Perico, Ariela Benigni, Giuseppe Remuzzi, Aldo Bonaventura, Alessandra Vecchi, Antonio Abbate, Zoya O. Serebrovska, Elisa Y. Chong, Lei Xi, Rafael Bellotti Azevedo, Bruna Gopp Botelho, Elizabeth Silaid Muxfeldt, Sarah Halawa, Soni S. Pullamsetti, Magdi H. Yacoub, Anglica Arcanjo, Jorgete Logullo, Alexandre Morrot, Toshifumi Matsuyama, Shawn P. Kubli, Tak W. Mak, Acta Pharmacologica Sinica 2021;178:38648. Oliveira MR, Back GD, da Luz Goulart C, Domingos BC, Arena R, Borghi-Silva A. Endothelial function provides early prognostic information in patients with COVID-19: A cohort study. Ikonomidis I, Pavlidis G, Katsimbri P, Lambadiari V, Parissis J, Andreadou I, et al. Plasma level of resistin is increased in COVID-19 patients and associated with disease severity as well as the expression of inflammatory cytokines (IL-6, IL-8 and MCP-1) and adhesion molecules (ICAM1 and VCAM1) [80]. The Erectile Dysfunction Drugs report tracks competitive progresses, strategies, mergers and acquisitions and new product development. sharing sensitive information, make sure youre on a federal Cardiovasc Res. Int J Mol Sci. Metformin represents the first-line therapy for T2DM [123]. Proc Natl Acad Sci USA. Chin Med. ACE2 is highly expressed in many major organs/tissues, including the heart, lung, kidneys. Aging Cell. Health Sci Rep. 2022;5:e762. Alexander MP, Mangalaparthi KK, Madugundu AK, Moyer AM, Adam BA, Mengel M, et al. 2021;6:402. Varga Z, Flammer AJ, Steiger P, Haberecker M, Andermatt R, Zinkernagel AS, et al. JAMA. 2021;22:4177. Management requires the immediate reduction of core temperature. Pine AB, Meizlish ML, Goshua G, Chang CH, Zhang H, Bishai J, et al. Signal Transduct Target Ther. Mol Neurobiol. 2020;18:23919. Mol Med (Camb, Mass). Eur Heart J. This study was supported by grants from National Key R&D Program of China (Grant No. Kondo Y, Larabee JL, Gao L, Shi H, Shao B, Hoover CM, et al. Acute brain dysfunction is highly prevalent in COVID-19 patients. It has been reported that the secretion of multiple markers of endothelial activation/dysfunction is elevated in COVID-19 patients, such as D-dimer (marker of coagulopathy and systemic thrombosis), vWF (a primary component of coagulation pathway and mediator of vascular inflammation and thrombo-inflammation released from Weibel-Palade bodies), factor VIII (marker of coagulation), PAI-1 (a marker of endothelial damage and senescence), soluble thrombomodulin (sTM), soluble P-selectin (marker of platelet and endothelial activation), soluble ICAM1 (sICAM1, marker of endothelial inflammation), soluble VCAM1 (sVCAM1, marker of endothelial inflammation), angiopoietin-2 (Ang-2, marker of angiogenesis and thrombosis), soluble E-selectin (sE-selectin, marker of endothelial inflammation), ET1 (a potent vasoconstrictor), VEGF-A (marker of angiogenesis and endothelial hyperpermeability), IL-6 and IL-8 (markers of endothelial inflammation), MCP-1 (marker of endothelial inflammation), resistin (an adipokine associated with endothelial damage and vasoconstriction), nitrosylhemoglobin (HbNO), lactate, and syndecan-1 (marker of endothelial glycocalyx damage) [19, 23, 80, 102,103,104,105,106]. The endothelium, the widely-distributed organ of the human body, is essential for maintaining tissue homeostasis by producing a variety of vasoactive molecules. Thermoregulatory disorders and illness related to heat and - PubMed However, the pathophysiology of acute and post-acute manifestations of COVID-19 (long COVID-19 . The net consequence is the extravasation of inflammatory and immune cell infiltrations [74]. Analysis of ACE2 expression in autopsy tissues indicates that high expression of ACE2, transmembrane protease serine 2 (TMPRSS2) and associated endotheliitis in capillaries but less in arterioles/venules from COVID-19 patients, compared with COVID-19-free subjects. SARS-CoV-2 infection alters the balance of endothelial protective molecules and endothelial damaging molecules, leading to endothelial dysfunction. Fajgenbaum DC, June CH. Dexamethasone in hospitalized patients with Covid-19. 2020;5:e138070. Viruses. This dual-function mechanisms suggest the important role of L-SIGN as the molecular bridge between ACE2 and SARS-CoV-2 spike protein to allow for virus infection in the patients. Association of inpatient use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized With COVID-19. Glycocalyx degradation and shedding disrupts endothelial junctional stability and plays a pivotal role in various forms of cardiovascular diseases [111]. Milani GP, Macchi M, Guz-Mark A. Vitamin C in the treatment of COVID-19. However, several JAK/STAT inhibitors such as ruxolitinib, tofacitinib and baricitinib can suppress cytokine signaling cascade. Pathway enrichment analysis revealed that SARS-CoV-2 infection upregulates expression of genes enriched in signaling pathways relevant to inflammatory response (such as NF-kappa B signaling pathway, TLR signaling pathway, NLRP3 pathway, NOD-like receptor signaling pathway and cytokinecytokine receptor interaction) [75]. Lancet Rheumatol. 2022;79:361. Hyperpyrexia is an elevation of body temperature above 106.7F (41.5C) due to an abnormally increased hypothalamic-thermoregulatory set. The purpose of this review is to provide a latest summary of biomarkers associated with endothelial cell activation in COVID-19 and offer mechanistic insights into the molecular basis of endothelial activation/dysfunction in macro- and micro-vasculature of COVID-19 patients. Frisoni P, Neri M, DErrico S, Alfieri L, Bonuccelli D, Cingolani M, et al. Batabyal R, Freishtat N, Hill E, Rehman M, Freishtat R, Koutroulis I. Metabolic dysfunction and immunometabolism in COVID-19 pathophysiology and therapeutics. Fiorentino G, Coppola A, Izzo R, Annunziata A, Bernardo M, Lombardi A, et al. 2020;32:53747. In vivo, SARS-CoV-2-infected K18 mice develop severe COVID-19 and endothelial dysfunction in pulmonary vessels suggested by VCAM-1 and ICAM-1 upregulation and VE-cadherin downregulation [78]. Recent studies have demonstrated that complement activation is associated with SARS-CoV-2 infection induced inflammation, endothelial injury, hypercoagulability and thrombosis [95]. Cytokine storm and histopathological findings in 60 cases of COVID-19-related death: from viral load research to immunohistochemical quantification of major players IL-1, IL-6, IL-15 and TNF-. Circ Res. EClinicalMedicine. 2021;398:599607. COVID-19 and thermoregulation-related problems: Practical 2022;3:100663. In the . doi: 10.1097/MD.0000000000033345. COVID-19 is also associated with liver injury. Evaluating the short-term effect of ambient temperature on non-fatal outdoor falls and road traffic injuries among children and adolescents in China: a time-stratified case-crossover study. These include tachycardia, shortness of breath, fatigue and post-exercise exhaustion. Int J Infect Dis. 2022;11:1972. Article Resistin is peptide hormone derived from adipose tissue which is associated with endothelial injury and inflammatory response. Keywords: Hu B, Huang S, Yin L. The cytokine storm and COVID-19. COVID-19 and thermoregulation-related problems: Practical Nat Neurosci. 2021;348:109657. 2022;9:826218. PubMed SARS-CoV-2 spike promotes inflammation and apoptosis through autophagy by ROS-suppressed PI3K/AKT/mTOR signaling. Anti-coagulatory or anti-hypertensive drugs treatment before admission leads to reduced number of CECs, indicating that COVID-19-associated coagulopathy and endotheliopathy could be ameliorated by anti-coagulatory or anti-hypertensive therapy [115]. Kidney Int. Tetlow S, Segiet-Swiecicka A, OSullivan R, OHalloran S, Kalb K, Brathwaite-Shirley C, et al. Anakinra for severe forms of COVID-19: a cohort study. The clinical detection of thermoregulatory impairment provides important diagnostic and localizing information in the evaluation of disorders that impair thermoregulatory pathways, including autonomic neuropathies and ganglionopathies. The year in cardiovascular medicine 2021: heart failure and cardiomyopathies. Schnaubelt S, Oppenauer J, Tihanyi D, Mueller M, Maldonado-Gonzalez E, Zejnilovic S, et al. Stahl K, Gronski PA, Kiyan Y, Seeliger B, Bertram A, Pape T, et al. When endothelial dysfunction/endotheliopathy/endotheliitis occurs in COVID-19, several markers of endothelial cell activation are used for assessing endothelial dysfunction in COVID-19 (Figs. Mechanistically, fluvoxamine is a sigma-1 receptor (S1R) agonist which, on the one hand, reduces the expression of IL-6, while increasing that of eNOS. Injury to the endothelial glycocalyx in critically Ill patients with COVID-19. Aging Dis. J Hepatol. 2021;9:1438. Virus-induced senescence is a pathogenic trigger of endothelial dysfunction. Mone P, Gambardella J, Wang X, Jankauskas SS, Matarese A, Santulli G. miR-24 targets the transmembrane glycoprotein neuropilin-1 in human brain microvascular endothelial cells. Google Scholar. COVID-19-associated coagulopathy (CAC) is a life-threatening complication of SARS-CoV-2 infection. Vasc Pharmacol. Thermoregulatory physiology sustains health by keeping body core temperature within a degree or two of 37C, which enables normal cellular function. 2020;7:559811. 2022. https://doi.org/10.1164/rccm.202107-1774OC. 2022;75:103812. One universal mechanism of endothelial inflammation in COVID-19 patients is plausibly associated with the downregulation of KLF2 [81], a master regulator of vascular homeostasis. Dexamethasone treated group exhibited a significantly decreased levels of various markers associated with endothelial dysfunction, including Ang-2, ICAM-1, and sRAGE [135]. The pathophysiology, impact, and outcomes of hyperpyrexia in patients with COVID-19 have not yet been studied. 2022;43:217390. 2020;41:303844. Top manufacturers . Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection represents an ongoing public health burden leading to extensive morbidity and mortality worldwide [1]. Recently, miR-98-5p was identified as a negative regulator of TMPRSS2 gene transcription in human lung and umbilical vein ECs [98]. The site is secure. 2023 Mar 31;102(13):e33345. In COVID-19 patients, heart failure and myocardial injury are frequent complications, underscoring the clinical utility of SGLT2 inhibitors [128]. The authors observed elevated levels of markers of coagulopathy/endotheliopathy and liver injury (ALT) in COVID-19 patients. Potential mechanisms of coronavirus disease 2019 (COVID-19)-induced olfactory dysfunction. Endothelial dysfunction in COVID-19: a unifying mechanism and a potential therapeutic target. Front Cardiovasc Med. Markers of endothelial cell activation are associated with the severity of pulmonary disease in COVID-19. These data agree with recent report of the clinical benefits of statin therapy in lowering the risk of mortality of COVID-19 [119]. Endothelial cells are sentinels lining the innermost layer of blood vessel that gatekeep micro- and macro-vascular health by sensing pathogen/danger signals and secreting vasoactive molecules. 2021;28:e12654. We determined the pooled prevalence of such chemosensory deficits in a systematic review and meta-analysis. Tan R, Xiang X, Chen W, Yang Z, Hu W, Qu H, et al. 2021;31:41532. N Engl J Med. 2020;32:17687. COVID-19 can present with multiple manifestations arising from endothelial dysfunction/endotheliopathy as below (Fig. 2022;36:e22052. This work was also supported by Program for Innovative Research Team of The First Affiliated Hospital of USTC (CXGG02), Anhui Provincial Key Research and Development Program (Grant No. Risk of acute myocardial infarction and ischaemic stroke following COVID-19 in Sweden: a self-controlled case series and matched cohort study. Tocilizumab also protects against endothelial dysfunction by increasing glycocalyx thickness and reducing the burden of inflammation and oxidative stress. J Med Virol. Caccuri F, Bugatti A, Zani A, De Palma A, Di Silvestre D, Manocha E, et al. Google Scholar. 2021;6:266. This site needs JavaScript to work properly. Circulating level of Angiopoietin-2 is associated with acute kidney injury in coronavirus disease 2019 (COVID-19). 2021;73:92467. 2021;93:2506. Poloni TE, Medici V, Moretti M, Vison SD, Cirrincione A, Carlos AF, et al. ISSN 1745-7254 (online) ET. 2020;222:178993. Circulatory exosomes from COVID-19 patients trigger NLRP3 inflammasome in endothelial cells. Huang Q, Wu X, Zheng X, Luo S, Xu S, Weng J. Front Endocrinol. SARS-CoV-2 causes ACE/ACE2 balance disruption and RAAS activation, which leads ultimately to COVID-19 progression, especially in patients with comorbidities, such as hypertension, diabetes mellitus, and cardiovascular disease. Heterogeneous ACE2 expression and endothelial damage was observed in COVID-19 autopsy tissues. 2020;73:123140. PubMed MacKenzie MA, Hermus AR, Wollersheim HC, Binkhorst RA, Pieters GF. Phytother Res. Dupont A, Rauch A, Staessens S, Moussa M, Rosa M, Corseaux D, et al. SARS-CoV-2 spike protein induces degradation of junctional proteins that maintain endothelial barrier integrity. These findings suggest that fluvoxamine can be repurposed as novel anti-COVID-19 drugs although further studies are warranted to assess the therapeutic potential of fluvoxamine in patients [151]. The disrupted glycocalyx structure leads to hyperinflammatory response and oxidative stress, which leads to increased susceptibility to SARS-CoV-2 infection [67]. Direct or indirect mechanism after SARS-CoV-2 infection and the consequent endotheliitis/endotheliopathy incites multiple instances of endothelial dysfunction, including altered vascular tone, oxidative stress, inflammation/leukocyte adhesion, endothelial mesenchymal transition (EndoMT), mitochondria dysfunction, virus-induced senescence, cytokine storm, and coagulopathy [12, 13]. In addition, with the progress of aging, the expression of ACE2 was increased in the pulmonary vascular ECs with the possible involvement of interleukin 7 via an NF-B-dependent manner, which can be blocked by Vitamin C [49]. Eur Respir J. HHS Vulnerability Disclosure, Help Slider with three articles shown per slide. Ma L, Sahu SK, Cano M, Kuppuswamy V, Bajwa J, McPhatter J, et al. Cell Res. 5. Cells. The effect of glucocorticoids on COVID-19 might be multifactorial, and their endothelium-stabilizing properties by direct activation of endothelial glucocorticoid receptors to block production of IL-6 and VEGF might be the main operating mechanisms [19]. In addition, S1 subunit of SARS-CoV-2 spike protein (S1) decreased endothelial barrier function in cultured human pulmonary microvascular ECs [22]. DAgnillo F, Walters KA, Xiao Y, Sheng ZM, Scherler K, Park J, et al. In addition to the above drugs discussed, there are several other reports showing that serine protease inhibitors (camostat mesylate), KLF2 activators [120], RIPK3 inhibitors [166], spironolactone [77], glycocalyx repairing drugs [67], purified glycosaminoglycan mixture sulodexide [167], CCR5 blockers (Maraviroc), anti-VEGF (bevacizumab [168]), adrecizumab [169], mesenchymal stem cell therapy [170], estrogen [171], melatonin [172] and NO donor [173] could also be beneficial (Fig. SARS-CoV-2 infection relies on ACE2 expression in ECs [48]. IL-6 trans-signaling induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome. 6). Heparanase is a putative mediator of endothelial glycocalyx damage in COVID-19 - A proof-of-concept study. Like other types of organ injury, SARS-CoV-2 infection causes AKI by both direct and indirect mechanisms, including endotheliitis, thrombosis and glucolipid derangement. The PAI-1 level in COVID-19 patients were as highly elevated compared with other cytokine release syndrome (sepsis or ARDS). Bethesda, MD 20894, Web Policies Front Cardiovasc Med. 2021;13:1172. Interestingly, the secretion of these cytokines is elevated in COVID-19 patients. 2022;10:e42e51. Endothelial dysfunction in COVID-19: Current findings and therapeutic implications. Deaths from hypothermia are twice as frequent as deaths from hyperthermia. Lancet Rheumatol. This shows that olfactory and especially gustatory disorders have to be seen as important chronic symptoms post-COVID-19. 3). Therefore, IL-6 trans-signaling represents the mechanistic link between the coagulopathy/endotheliopathy and COVID-19 associated liver injury [35]. Liu Y, Zhang HG. EBioMedicine. Biochimica et Biophysica Acta Mol Basis Dis. 2017;12:e0186116. It is well-established that SARS-CoV-2 enters host cells including ECs via ACE2 and coreceptor TMPRSS2. 2022;9:866113. A significant proportion of people who test positive for COVID-19 have chemosensory deficits. Kang S, Kishimoto T. Interplay between interleukin-6 signaling and the vascular endothelium in cytokine storms. Shao Y, Saredy J, Xu K, Sun Y, Saaoud F, Drummer CT, et al. 1996;109:34-8. Basta G. Direct or indirect endothelial damage? Acta Pharmacol Sin. The American-European Consensus Conference definition of the acute respiratory distress syndrome is dead, long live positive end-expiratory pressure! Recent studied have shown that colchicine is able to reduce the length of stay in hospitalized COVID-19 patients with the possible mechanism of inhibition of NLRP3 inflammasome and resultant IL-1 production [143, 144]. All the above evidence pinpoints the protective effect of heparin in COVID-19 could largely be attributable to glycocalyx-stabilizing effect. Oxid Med Cell Longev. FASEB J. SASP senescence-associated secretory phenotype. Cells. The enigma of the SARS-CoV-2 microcirculation dysfunction: evidence for Google Scholar. Costa TJ, Potje SR, Fraga-Silva TFC, da Silva-Neto JA, Barros PR, Rodrigues D, et al. In these cardiovascular complications, endothelial dysfunction plays a fundamental role [27]. J Infect Dis. Kang X, Jin D, Jiang L, Zhang Y, Zhang Y, An X, et al. Ilonzo N, Judelson D, Al-Jundi W, Etkin Y, OBanion LA, Rivera A, et al. Persisting olfactory dysfunction in post-COVID-19 is associated - PLOS Evaluation of endothelial dysfunction in COVID-19 with flow-mediated dilatation. SARS-CoV-2 spike protein impairs endothelial function via downregulation of ACE 2. Cardiovasc Res. Ngele MP, Haubner B, Tanner FC, Ruschitzka F, Flammer AJ. It is well-known that IL-1 induces the expression of itself and other pro-inflammatory and pro-adhesive molecules, such as TNF-, leading to the amplification of cytokine storm. 2021;24:152233. Chen L, Li X, Chen M, Feng Y, Xiong C. The ACE2 expression in human heart indicates new potential mechanism of heart injury among patients infected with SARS-CoV-2. PubMed Cell Mol Life Sci. bioRxiv: the preprint server for biology 2021. https://doi.org/10.1101/2021.12.10.472112. Ni W, Yang X, Yang D, Bao J, Li R, Xiao Y, et al. Stem Cell Rep. 2021;16:245972. Lee S, Yu Y, Trimpert J, Benthani F, Mairhofer M, Richter-Pechanska P, et al. Vasculopathy in COVID-19. Many patients with severe COVID-19 present with coagulation abnormalities that mimic other systemic coagulopathies associated with severe infections, such as disseminated intravascular coagulation (DIC) or thrombotic microangiopathy, but COVID-19 has distinct features. These results suggest that statins can be exploited to treat COVID-19 patients by mitigating endotheliopathy [45, 121]. 2021;13:2209. TCM has a well-documented safety profile in protecting against COVID-19 on the basis of standard care. Biomolecules. 2020;21:9712. Pharmacol Rev. Noris M, Benigni A, Remuzzi G. The case of complement activation in COVID-19 multiorgan impact. Signal Transduct Target Ther. A recent study has shown that SARS-CoV-2-infection of human brain microvascular ECs showed augmented caspase 3 cleavage and apoptotic cell death of endothelial cells. Therefore, the therapeutic role of JIVC in treating severe COVID-19 patients warrants further investigation [160]. 2021;16:e0253524. Non-coding RNA. Exp Mol Med. Correspondence to Endothelial cell number is determined by the balance of cell proliferation and cell death. 2020;21:8793. The glycocalyx, a protective microstructure layer on the vascular endothelium, consists of glycoproteins and regulates capillary homeostasis by controlling vascular inflammation [109]. Coagulation abnormalities and thrombosis in patients with COVID-19 Am J Respir Crit Care Med. 2022;10:812. de Rooij L, Becker LM, Carmeliet P. A role for the vascular endothelium in post-acute COVID-19? Xu J, Zhang J, Lin H, Zhang J, Zhou R, Wu X, Niu Y, Zhang J. Heparin prevents in vitro glycocalyx shedding induced by plasma from COVID-19 patients.
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