Article Metformin in cardiovascular diabetology: a focused review of its impact on endothelial function. Eur Respir J. 01 May 2023 01:18:34 Signal Transduct Target Ther. Zhang X, Jiang M, Yang J. COVID-19 and Endothelial Cell Dysfunction Initial SARS-CoV-2 infection occurs within the lung epithelia, whereby serine proteases, most notably transmembrane protease serine 2 (TMPRSS2), cathepsin B, and cathepsin L1, prime the SARS-CoV-2 spike glycoprotein, which is followed by ACE2-mediated viral entry ( 29 ). In terms of the important role of EndoMT in multiple vascular diseases, further mechanistic characterization of EndoMT in COVID-19 patients as well as convalescent patients is urgently needed. Resistin associated with cytokines and endothelial cell adhesion molecules is related to worse outcome in COVID-19. 2021;29:894907. Recently, miR-98-5p was identified as a negative regulator of TMPRSS2 gene transcription in human lung and umbilical vein ECs [98]. Qin H, Zhao A. Mesenchymal stem cell therapy for acute respiratory distress syndrome: from basic to clinics. McConnell MJ, Kawaguchi N, Kondo R, Sonzogni A, Licini L, Valle C, et al. 2020;126:167181. Direct SARS-CoV-2 infection or indirect effect arising from SARS-CoV-2 infection leads to endothelial dysfunction in pan-vasculature, which results in the development of multi-organ tissue injury. Till now, several TCM have shown good therapeutic effects in COVID-19, such as Lianhua Qingwen, Xuebijing Injection, Shuanghuanglian, Jinyinhua and Qingfei Paidu Decoction [161,162,163,164]. It is well-established that SARS-CoV-2 enters host cells including ECs via ACE2 and coreceptor TMPRSS2. Hyperpyrexia is an elevation of body temperature above 106.7F (41.5C) due to an abnormally increased hypothalamic-thermoregulatory set. Pharmacol Res. Semin Vasc Surg. 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. Eligibility PubMedGoogle Scholar. 1996 Oct-Nov;82(10-11):108-14. Clin (Sao Paulo, Braz). Fodor A, Tiperciuc B, Login C, Orasan OH, Lazar AL, Buchman C, et al. 2021;599:2839. 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]. Cell. Article Interleukin-1RA mitigates SARS-CoV-2-induced inflammatory lung vascular leakage and mortality in humanized K18-hACE-2 mice. Role of angiotensin-converting enzyme 2 (ACE2) in COVID-19. PMC A recent randomized clinical trial has shown that heparin treatment was not significantly associated with reduction of primary outcome, but associated with decreased odds of death at 4 weeks [129]. Melatonin drugs inhibit SARS-CoV-2 entry into the brain and virus-induced damage of cerebral small vessels. 2022;96:3441. 2021YFC2500500), National Natural Science Foundation of China (Grant No. Therapeutic potential of colchicine in cardiovascular medicine: a pharmacological review. SARS-CoV-2 can cross the blood brain barrier without affecting the expression of tight junctions (claudin5, ZO-1 and occludin) [41]. Kang S, Tanaka T, Inoue H, Ono C, Hashimoto S, Kioi Y, et al. Thus, COVID-19 is deemed as a (micro)vascular and endothelial disease. Acute myocardial infarction and myocarditis following COVID-19 vaccination. In this regard, miR-24-3p has recently been identified as an essential regulator of Neuropilin-1 gene transcription, thereby maintaining barrier integrity via suppressing VEGF-induced endothelial leakage in human brain ECs [99]. From a study cohort (consisting of 76% male and 24% female individuals), there was at least one abnormality of diaphragm muscle function on structure visualized by ultrasound in 80% of cases. This study highlights the crucial role of IL-6 trans-signaling in endothelial dysfunction/endotheliopathy in COVID-19 [137]. Ackermann M, Verleden SE, Kuehnel M, Haverich A, Welte T, Laenger F, et al. Effect of early treatment with fluvoxamine on risk of emergency care and hospitalisation among patients with COVID-19: the TOGETHER randomised, platform clinical trial. 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 PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). 2022;25:22540. To obtain 2020;32:53747. Xu S, Liu Y, Ding Y, Luo S, Zheng X, Wu X, et al. 2022;11:1972. 2020;40:24047. Further outstanding questions and research directions in the realm of endothelial dysfunction and COVID-19 include the following: The development of assays of assessing endothelial function in long COVID-19 patients and convalescents, such as brachial artery flow-mediated dilation (FMD) and arterial stiffness [carotid-femoral pulse wave velocity (cfPWV)]; This aspect is important considering the recent observation showing the decreased FMD in patients with COVID-19 stemming from expression of inflammatory cytokines/chemokines [176]; Cellular and animal models of evaluating endothelial dysfunction in COVID-19 to accelerate drug discovery; The therapeutic potential of specialized pro-resolving lipid mediators, such as resolvin D1, resolvin E1, aspirin-triggered resolvin D1 in resolving cytokine storm induced inflammatory responses can be pursued; The identification of alternative receptors for SARS-CoV-2 infection into different vascular beds beyond known ones (such as ACE2, AXL and L-SIGN) remain to be identified; Drug repurposing or high-throughput drug screening to identify new drugs targeting endothelial dysfunction in COVID-19; The role of epigenetic modification arising from DNA methylation and histone modification and long-lasting epigenetic memory effects caused by SARS-CoV2 infection in long COVID (postacute COVID-19 syndrome) remain to be evaluated [7]; Metabolic disturbance has been shown to be associated with the pathogenesis of COVID-19 [177]. Front Cardiovasc Med. Pathol Res Pract. Instead, ACEIs/ARBs discontinuation is associated with poorer clinical outcomes. 2021;6:e148999. Han T, Ma S, Sun C, Zhang H, Qu G, Chen Y, et al. ACE2 angiotensin-converting enzyme-2, ACEI angiotensin converting enzyme inhibitors, ARB angiotensin receptor blockers, BRD4i bromodomain-containing protein 4 inhibitors, JAK janus kinase, SGLT2i sodium-glucose cotransporter-2 inhibitors. 2022;43:36776. 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. COVID-19 can manifest with myocardial injury (ischemic heart disease, arrhythmias and cardiomyopathies), arterial stiffness, liver injury and kidney injury [3]. Of translational significance, COVID-19 patients derived serum also increased mtDNA release in ECs, compared to control subjects. 2021;128:13236. Corrao S, Pinelli K, Vacca M, Raspanti M, Argano C. Type 2 diabetes mellitus and COVID-19: a narrative review. Vitamin C and COVID-19. The authors declare no competing interests. Thermoregulatory physiology sustains health by keeping body core temperature within a degree or two of 37C, which enables normal cellular function. Based on the evidence presented, there was heterogenous ACE2 expression in ECs from various vascular beds. Chang R, Mamun A, Dominic A, Le NT. Kandhaya-Pillai R, Yang X, Tchkonia T, Martin GM, Kirkland JL, Oshima J. TNF-/IFN- synergy amplifies senescence-associated inflammation and SARS-CoV-2 receptor expression via hyper-activated JAK/STAT1. 2022;19:149. 2021;12:18506. However, the pathophysiology of acute and post-acute manifestations of COVID-19 (long COVID-19 . In addition, plasma profiling study of patients with COVID-19 revealed elevated circulating levels of markers of angiogenesis (such as VEGF-A) in COVID-19 patients [84]. Kondo Y, Larabee JL, Gao L, Shi H, Shao B, Hoover CM, et al. 2022;43:217390. Front Med. Mansiroglu AK, Seymen H, Sincer I, Gunes Y. Int J Obes (2005). A recent study [35] has reported that IL-6 trans-signaling in LSECs leads to endotheliopathy and liver injury in COVID-19 patients. 2020;24:422. Activated cytokine storm and IL-6 signaling has been observed in endothelial dysfunction during bacterial infection and SARS-CoV-2 infection [92]. Nutr J. QJM. Tocilizumab improves oxidative stress and endothelial glycocalyx: A mechanism that may explain the effects of biological treatment on COVID-19. Ambrosino P, Calcaterra IL, Mosella M, Formisano R, DAnna SE, Bachetti T, et al. 2017BT01S131), Hefei Comprehensive National Science Center (Grant No. 2021;28:e12654. 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]. Large-scale clinical trials are warranted to evaluate whether the use of SGLT2 inhibitors can reduce the mortality and hospitalizations for heart failure in COVID-19 patients with or without T2DM. Mechanistically, patients with heart failure demonstrate increased ACE2 gene and protein expression, suggesting that if patients with heart failure were infected by the virus, they are more susceptible to severe COVID-19 and develop into a critically-ill conditions [28]. Mitochondrial DNA and TLR9 activation contribute to SARS-CoV-2-induced endothelial cell damage. The IL-1, IL-6, and TNF cytokine triad is associated with post-acute sequelae of COVID-19. The most common clinical presentation of severe COVID-19 is acute respiratory failure consistent with the acute respiratory distress syndrome. Furthermore, it has been demonstrated that exosomes from severe COVID-19 patients trigger the activation of caspase-1 and NLRP3 inflammasome and release of IL-1 in ECs [64]. 2022;55:57. 2020;8:462. An unresolved question. Effect of SARS-CoV-2 proteins on vascular permeability. Deaths from . Another recent study has demonstrated that, SARS-CoV-2 infection in human brain microvascular ECs increased the secretion of angiogenic factors and altered mitochondrial dynamics, such as increased the expression of mitofusin-2 (a protein involved in a maintenance of an appropriate mitochondrial architecture, metabolism and signaling) and fostered the formation of mitochondrial networks [65]. J Inflamm Res. Pulm Circ. Front Immunol. Charfeddine S, Ibnhadjamor H, Jdidi J, Torjmen S, Kraiem S, Bahloul A, et al. PubMed National Library of Medicine On the other hand, S1R agonism by fluvoxamine activates Akt-eNOS signaling in mouse aorta in a S1R-dependent manner. It has been recently reviewed that restoration of balanced effects between the RAAS and ACE2/Ang-(17)/MAS could be a promising way to ameliorate multi-organ injury associated with COVID-19 [130]. Breithaupt-Faloppa AC, Correia CJ, Prado CM, Stilhano RS, Ureshino RP, Moreira LFP. 2021;13:eabj7790. Thus, the endothelium is regarded as the Achilles heel in COVID-19 patients [8]. Article HHS Vulnerability Disclosure, Help In addition, the release of inflammatory cytokines after severe SARS-CoV-2 infection leads to cytokine storm, tight junction barrier disruption, pulmonary hypertension, and lung fibrosis [24]. Schattner A. Colchicine-new horizons for an ancient drug. Lenze EJ, Mattar C, Zorumski CF, Stevens A, Schweiger J, Nicol GE, et al. Viruses. Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. 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. Signal Transduct Target Ther. Several histopathological evidence has supported direct viral infection of endothelial cells, for example, electron microscopy of kidney tissues shows the existence of endotheliitis and viral particles in ECs [52]. Trends Microbiol. Department of Endocrinology, Institute of Endocrine and Metabolic Diseases, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, Clinical Research Hospital of Chinese Academy of Sciences (Hefei), University of Science and Technology of China, Hefei, 230001, China, You can also search for this author in Cells. Front Immunol. JAK/STAT pathway is a canonical pathway in driving inflammation. Aging Dis. A recent study has shown that markers associated with endothelial inflammation and injury pathway (IL-6, TNF-, ICAM-1 and caspase-1) were observed in the lung tissues from COVID-19 patients compared with H1N1 subtype 2009 and control cases [63]. 2020;383:225573. Endothelial dysfunction as a primary consequence of SARS-CoV-2 Infection. Barbosa LC, Gonalves TL, de Araujo LP, Rosario LVO, Ferrer VP. Combinatorial treatment of human ECs with TNF- and IFN- increased the expression of ACE2, the receptor mediating viral entry via JAK/STAT1 pathway [13]. Ma L, Sahu SK, Cano M, Kuppuswamy V, Bajwa J, McPhatter J, et al. 2021;163:15362. The glycocalyx consists of highly sulfated proteoglycans with glycosaminoglycan side chains. Interestingly, live SARS-CoV-2 virus and sera from COVID-19 patients, but not dead virus or spike protein triggers increased endothelial permeability [20, 23]. Potential value of circulating endothelial cells for the diagnosis and treatment of COVID-19. CAS Effectiveness and safety of traditional chinese medicine in treating COVID-19: clinical evidence from China. One of the most peculiar characteristics of the olfactory dysfunction in COVID-19 is that it typically starts very abruptly, lasts for only a few days (mean or median ranges: 7-21.6 days [34,35]), and smell can recover just as abruptly as it was lost. XDB38010100). 2021;276:119376. du Preez HN, Aldous C, Hayden MR, Kruger HG, Lin J. Pathogenesis of COVID-19 described through the lens of an undersulfated and degraded epithelial and endothelial glycocalyx. Basta G. Direct or indirect endothelial damage? COVID19 has infected at least 25,248,595 persons worldwide through August 31, 2020, causing 846,877 deaths. 2021;398:599607. Endothelial dysfunction is generally defined as decreased NO bioavailability and an increase in vasoconstrictory substances (such as endothelin-1 (ET1), angiotensin II (AngII) and many others). SARS-CoV-2 infection can also cause acute kidney injury (AKI). Kaundal RK, Kalvala AK, Kumar A. Arch Med Res. Physiological functions of the endothelium include fine control of vascular tone, tissue hemostasis, barrier integrity, inflammation, oxidative stress, vascular permeability, and structural and functional integrity [4]. Electron microscopy also show coronaviruses and vesicles containing virion particles in venous ECs [53] as well as LSECs from liver autopsy samples from COVID-19 patients [33]. Int J Mol Sci. 2022;13:926189. Single-cell transcriptomic atlas of primate cardiopulmonary aging. In addition, COVID-19 is an important risk factor for developing acute myocardial infarction [29]. Heparanase is a putative mediator of endothelial glycocalyx damage in COVID-19 - A proof-of-concept study. Copyright 2016 The Author. J Neuroinflammation. Potje SR, Costa TJ, Fraga-Silva TFC, Martins RB, Benatti MN, Almado CEL, et al. 2021;73:92467. Interestingly, the secretion of these cytokines is elevated in COVID-19 patients. Cecon E, Fernandois D, Renault N, Coelho CFF, Wenzel J, Bedart C, et al. Vitamin C consumption significantly reduces mortality risk with COVID-19 patients [157]. Endothelial cell infection and dysfunction, immune activation in severe COVID-19. Several large-scale clinical trials have suggested that glucocorticoid drug dexamethasone treatment is beneficial for COVID-19 patients [134]. IL-6 directly impacts vascular ECs by promoting the production of numerous cytokines/chemokines/adhesion molecules essential for promoting leukocyte adhesion, vascular leakage and activating the coagulation cascade [136]. Khider L, Gendron N, Goudot G, Chocron R, Hauw-Berlemont C, Cheng C, et al. Lancet Rheumatol. Cytokine storm in COVID-19 can trigger inflammation via the JAK/STAT pathway, which results in increased recruitment of leukocytes/immune cells [146]. Schimmel L, Chew KY, Stocks CJ, Yordanov TE, Essebier P, Kulasinghe A, et al. Eapen MS, Lu W, Gaikwad AV, Bhattarai P, Chia C, Hardikar A, et al. By doing so, anakinra significantly increased the survival rate of infected mice [140]. J Hepatol. 7). Google Scholar. Fang W, Jiang J, Su L, Shu T, Liu H, Lai S, et al. J Mol Cell Cardiol. 2021;221:153419. Dexamethasone treated group exhibited a significantly decreased levels of various markers associated with endothelial dysfunction, including Ang-2, ICAM-1, and sRAGE [135]. Deaths from hypothermia are twice as frequent as deaths from hyperthermia. Endothelial dysfunction-induced endotheliitis/endothelialitis/endotheliopathy following SARS-CoV-2 infection arises from a plethora of physiopathological mechanisms, including both direct mechanism of virus infection or indirect mechanisms such as paracrine effects of infected cells [2, 68]. These findings suggest that spike protein interactions with ECs contribute to inflammation, thrombosis, and the severity of COVID-19 and could offer novel mechanistic insights into SARS-CoV-2 induced vascular leakage and the development of targeted therapies [59]. Employing mechanical ventilation techniques on venovenous extracorporeal membrane oxygenation (VV ECMO . Front Physiol. Stem Cell Rep. 2021;16:245972. Ice water immersion has been shown to be superior to alternative cooling measures. Pharmacological inhibition of senescence or SASP can reverse endothelial inflammation and leukocyte adhesion. Use the Previous and Next buttons to navigate the slides or the slide controller buttons at the end to navigate through each slide. Validated psychophysical testing revealed hyposmia in 18% and hypogeusia in even 32% of 303 included patients. 2021;27:151. 2021;24:4036. ADMA asymmetrical dimethylarginine, AngII angiotensin II, Angpt-2 angiopoietin-2, CAT catalase, EDHF endothelium-derived hyperpolarizing factor, eNOS endothelial nitric oxide synthase, ET-1 endothelin 1, GCH1 GTP cyclohydrolase 1, H2S hydrogen sulfide, HO-1 heme oxygenase-1, ICAM1 intercellular adhesion molecule 1, KLF2 krppel-like factor 2, NO nitric oxide, Nrf2 nuclear factor erythroid 2-related factor 2, PAI-1 plasminogen activator inhibitor 1, PGI2 prostaglandin I2, ROS reactive oxygen species, SOD superoxide dismutase, TF tissue factor, Thbd thrombomodulin, Tie-2 tyrosine-protein kinase receptor, tPA tissue plasminogen activator, Tx-A2 thromboxane A2, uPA urokinase plasminogen activator, VCAM1 vascular cell adhesion molecule 1, vWF von Willebrand factor.

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