Introduction
The World Health Organisation (WHO) has declared the COVID-19 as a global pandemic. The International Committee on Taxonomy of Viruses renamed the virus as SARS-CoV-2 due to the aetiology and the symptoms. The SARS-CoV-2 is a positive-sense single stranded Ribonucleic Acid (RNA) (30 kb) enveloped virus which belongs to the β coronavirus family with a diameter of 50-220 nm. The spike glycoprotein (S1 and S2 heterodimers) is a key structural protein of this virus, which make it more pathogenic [1,2]. However, this is not the first time when coronavirus has infected humans. With common cold like symptoms, coronavirus was first reported in the year 1966 by Tyrell and Bynoe. Later in the year 2003, SARS-CoV-1 and the year 2012, the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) had infected people of many countries [3]. Interestingly, the genome of SARS-CoV-2 reported being associated with the genome of SARS-CoV-1 and MERS-CoV [1]. Worldwide, more than 3,000,000 people were infected and more than 2,00,000 people were killed by COVID-19, suggesting the severity of SARS-CoV-2 [4].
Meta-analysis on patients with COVID-19 elucidated CVDs as a major risk factor for severe COVID-19 infection. A meta-analysis of 76993 patients with COVID-19 reported that the prevalence of CVD was 12.11%, and hypertension was 16.37% [5]. Another study on 44672 patients reported that the prevalence of CVD was 10.5%, and hypertension was 6% [6]. Other studies show similar findings suggesting that pre-existing CVDs may be a risk factor for elevated mortality rate in COVID-19 disease [7-10]. Moreover, obesity has been considered as a prominent risk factor for the development and the progression of cardiovascular complications clustering myocardial infarction, dysrhythmias, carditis, heart failure venous thrombosis and thromboembolic disease [11]. Therefore, this review focuses on the functional, biochemical and pathophysiological aspects of the obesity mediated CVDs and their effects on the COVID-19 severity.
Adipose Tissue Physiology and COVID-19
Adipose tissue is a vital organ typically involved in energy homeostasis of the body. In mammals, adipose tissues are classified as Brown Adipose Tissue (BAT) and White Adipose Tissue (WAT). BAT is enriched with mitochondria and active uncoupling proteins, hence appear brown and generate heat via non-shivering thermogenesis respectively. Conversely, WAT is subdivided as visceral and subcutaneous fat depots and is principally involved in altered lipid metabolism (dyslipidemia) and obesity [12]. However, to store excess energy preadipocytes potentially differentiate in mature adipocyte, under the strict control of CCAAT/Enhancer-Binding Proteins (C/EBPs) and Peroxisome Proliferator Activated Receptor gamma (PPARγ) transcription factors. This leads to adipose tissue expansion through hyperplasia (increase in adipocyte number) and hypertrophy (increase in adipocyte volume/size), responsible for obesity and its associated co-morbidities [13]. Further, adipose tissue acts as an endocrine organ that secretes various hormones/adipocytokines/enzymes called “adipokines”. Elevated dyslipidemia and altered secretion of adipokines such as adiponectin, leptin, Plasminogen Activator Inhibitor-1 (PAI-1), IL-6 and visfatin have been reported as a major risk of CVDs in patients with obesity [14] and thus might be involved in the severity of COVID-19.
At present, there is no direct evidence explaining SARS-CoV-2 infection in adipose tissue, except Angiotensin Converting Enzyme-2 (ACE-2) receptor expression on several cells within this tissue, including mature adipocyte, macrophages, stromal vascular cells and endothelial cells [15,16]. Thus, the analysis of these cells may provide a possible interlinked mechanism between adipose tissue and the severity of COVID-19. Visceral adipose tissue is distributed specifically throughout the body. Hence, adipose tissue associated with lung might act as a SARS-CoV-2 reservoir and can modulate inflammatory responses, vascular wall dysfunction (atherosclerosis), CVDs and thereby, the severity of COVID-19 disease [17].
Dislipidemia, CVDs and COVID-19
Excess dietary FFA deposit in adipose tissue which is later transported to the liver. The Triglyceride (TG) rich lipoproteins (chylomicrons) derived from dietary FFA and cholesterol promotes fat storage in the adipose tissue, while catabolism of TG promotes mobilisation of FFA as a fuel to the tissues and organs; therefore, lipogenesis and the lipolysis are considered as the chief functions of the adipose tissue [18]. In the liver, FFA generates Very Low Density Lipoproteins (VLDL) consist of TG, cholesterol and apolipoprotein, suggesting hypertriglyceridemia. This lowers the amount of High Density Lipoproteins cholesterol (HDL-c) and increases the amount of Low Density Lipoproteins cholesterol (LDL-c) in serum, leading to dyslipidemia [19]. Conventionally, this altered lipid status has been reported for the diagnosis and the prognosis of the CVDs, atherosclerosis and hypertension [20]. Thus, determining dyslipidemia in patients with COVID-19 might give a link between CVDs and severity of this disease.
Almost all studies performed to determine dyslipidemia in patients with COVID-19 have shown the decreased levels of Total Cholesterol (TC), HDL-c and LDL-c [21-24]. These levels further decrease in critical and severe patients compared to mild patients, while putatively increases with the recovery of patients [25]. Also, higher monocyte/HDL-c ratio and the lower HDL-c levels in the primary infection cases than the secondary infection cases have also been reported [21]. Decreased LDL-c, HDL-c, and TC have been reported in many viral infections, including Hepatitis B Virus (HBV) and chronic illness such as cancer [26]. However, the role of cholesterol in the progression of viral infections has been well studied in Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV). The mechanism of the disease involves Scavenger Receptor B type 1 (SR-B1) binding site, HDL-c, free cholesterol and TG [27]. Further, membrane bound cholesterol has been reported to facilitate the entry of the virus in the host cell [28]. As far as SARS-Cov-2 is concerned, cholesterol facilitates the binding of SARS “S” protein with ACE-2, which allow the entry of the virus into the target cell (tongue/bronchi/lung). Also, a recent study showed that cholesterol metabolism regulating protein/enzyme decrease in human colon epithelial carcinoma cells infected with the SARS-CoV-2, which suggests the cholesterol modulatory effects of this virus [26]. Hence, a cholesterol lowering and ACE-2 upregulating drug like statin could be recommended as a therapeutic to prevent host cell infection and lung injury in patients with COVID-19 [29]. Conversely, Shrestha SK argued that the use of statin causes very low or no synthesis of endogenous cholesterol, resulting in the upregulation of LDL-c in the cell membrane [30]. Thus, the use of statin may increase the risk of COVID-19 by promoting host cell infection.
As per the standard lipid profile, decreased HDL-c and increased LDL-c is responsible for CVDs. However, in contrast to this, the patients with COVID-19 exhibit hypolipidemia. Decreased HDL-c favours CVD, while decreased LDL-c creates an enigma as it correlates with the increased severity of COVID-19 [26,31]. Further, as decreased level of cholesterol reduces the severity of host cell infection by SARS-CoV-2; however, patients with COVID-19 shows hypolipidemia, which warrants further investigations about the COVID-19 disease progression.
Adipokines, CVDs and COVID-19
Adipokines secreted by adipose tissue are reported for the pathophysiology of diabetes mellitus, non-alcoholic fatty liver diseases and CVDs [32]. Among various adipokines leptin, PAI-1, resistin, visfatin, hepcidin and chemerin have been reported for increased risk of CVDs via peripheral and central mechanisms, whereas adiponectin, omentin and IL-10 have been reported for their cardioprotective roles [33,34]. Therefore, altered secretion of adipokines during obesity could be used to correlate CVDs with the severity of COVID-19 and their possible pathophysiological mechanisms, of which adiponectin and leptin have received more importance [35]. Adiponectin exhibit an anti-inflammatory role by promoting secretion of anti-inflammatory cytokines like IL-10 and IL-1 receptor antagonist and by regulating pro-inflammatory cytokines like IL-6 and Tumour Necosis Factor alpha (TNF-α). On the contrary, leptin acts as a pro-inflammatory cytokine and thus modulates cellular immune responses by favouring synthesis of pro-inflammatory cytokines like TNFα, IL-2 as well as interferon-γ and by attenuating the synthesis of anti-inflammatory cytokines like IL-4 and IL-5 [36,37]. Hence, low grade chronic inflammation is a typical characteristic of obesity that affects the vessel wall and cardiovascular homeostasis. Also, leptin/adiponectin ratio has been proposed for adipose tissue dysfunction, lung injury and the progression of CVD [38]. Adiponectin helps in determining the mortality of patients with COVID-19 [39]. Thus, it could be predicted that CVD related COVID-19 severity may be due to the abnormal secretion of adipokines.
Adhesion Molecules, CVDs and COVID-19
Elevated expression of adhesion molecules like Vascular Cell Adhesion Molecule (VCAM), Intracellular Cell Adhesion Molecule (ICAM) and E-selectin are evidenced for progression and diagnosis of CVDs [40]. During chronic inflammation, adhesion molecules and pro-inflammatory cytokines guide circulating monocytes for their endothelial migration and differentiation into the macrophages [41]. Accumulation of macrophages increases the further burden of inflammation in endothelial cells leading to CVDs and atherosclerosis lesions [42]. As stated before, obesity exhibit low grade chronic inflammation and contribute to the pro-inflammatory cytokines like IL-6 as well as TNF-α, and, therefore, promote atherosclerosis, hypertension and CVDs via aforesaid adhesion molecule mediated mechanism [43]. However, the severity of obesity mediated endothelial dysfunction and CVDs are significantly increased by IL-6 and an adipocytokine Monocyte Chemoattractant Protein-1 (MCP-1). IL-6 stimulates monocyte to macrophage differentiation [43,44], while MCP-1 regulates cytokine and adhesion molecule expression [45]. IL-1 and IL-6 blockers may reduce inflammation [46].
Adipokines are also reported for their effects on adhesion molecule targeted vascular wall disease and CVDs. Among them, adiponectin has been documented for the decreased production of adhesion molecules, while resistin and ghrelin stimulate VCAM-1 expression and ghrelin alone can increase the ICAM expression [47,48]. Also, Lung marginated monocytes have been reported for acute lung injury [49]. This discussion suggests that obesity induced altered expression of cell adhesion molecules are responsible for chronic endothelial dysfunction, CVDs and lung injury. Interestingly, it has been revealed that the Influenza virus infection in alveolar epithelial cells facilitates monocyte migration and macrophagic differentiation. This transepithelial migration of monocyte is favoured by binding of monocyte β1, and β2 integrins and integrin associated protein with adhesion molecules (VCAM-1, ICAM-1, Cluster of Differentiation (CD47) and junctional adhesion molecule-c) expressed on the epithelial cells. The severity of this transepithelial monocyte infiltration is further accelerated by TNF-α [50,51]. Recently, Tong M et al., reported the elevated levels of VCAM-1, ICAM-1 and Vascular Adhesion Protein-1 (VAP-1) in patients with COVID-19 signifies the role of CVDs as a major risk of COVID-19 [52]. Although the authors did not explain the leading cause of higher adhesion molecules or inclusion/exclusion criteria related to obesity in the study, hence, a predicted cause associated with obesity might be postulated based on the above arguments.
RAS Mediated CVDs and COVID-19
The Rennin Angiotensin System (RAS) is a crucial mechanism operating in the body that regulates cardiovascular functions and contributes to a series of CVDs [53]. As ACE-1 works actively with the RAS system and a potent source for cellular SARS-CoV-2 invasion, discussing it could be another pathway that can contribute to the high COVID-19 severity via CVDs [54]. Usually, the RAS system is composed of Angiotensinogen (AGT), rennin, angiotensin-I (Ang-I), angiotensin-II (Ang-II), ACE I and II (ACE-I and ACE-II) and two Ang II receptors namely angiotensin type 1 receptor (AT-1) and Angiotensin Type 2 receptor (AT-2) [55,56]. The rennin is an enzyme which acts on a 1,2 AGT (a 452 amino acid-containing protein) to produce Ang-I. Ang-I (a decapeptide) acts as a substrate for ACE and produce Ang-II. Ang-II (an octapeptide) plays a pivotal role in distinct pathophysiological functions via AT-1 and AT-2 receptors [57,58].
Among these two receptors, binding of Ang-II to AT-1 receptor promotes vascular proliferation, growth, endothelial dysfunction and vasoconstriction, which are responsible for hypertension and atherosclerotic CVDs [59]. AT-2 acts reversely and favour tissue growth and repair mechanisms [60]. ACE-II inhibitors prevent the conversion of Ang-I into Ang-II and therefore can suppress the deleterious effects of Ang-II. Also, Ang-II inhibition stimulates the release of bradykinin, which shows vasodilatory and tissue protective effects [61,62]. Thus, attenuation of AT-1 and use of ACE inhibitors are considered as a potential therapeutic line for the treatment of RAS related disorders [60]. Further, both AT-I and AT-II receptors have been located in adipose tissue; suggesting local RAS [61]. Adipocytes are reported as a source for the synthesis of RAS components; however, synthesis is regulated with respect to the status of obesity and hypertension [62]. Ang-II exerts a crucial role in adipose tissue, including adipocyte growth and differentiation, adipokine release, lipid metabolism and different local RAS component production in the visceral and subcutaneous fat depot [63]. Hence, targetting a RAS might provide a link between obesity-related CVDs and severe SARS CoV-2 infection in patients.
Conclusion(s)
In summary, obesity is a chronic metabolic disorder responsible for CVDs via low state chronic inflammation. Studies on current COVID-19 pandemic shows various major risk factors that are associated with increased severity of SARS-CoV-2 infection in patients. Obesity makes favourable conditions for the development of the CVDs, however, these favourable conditions may contribute in the progression of COVID-19 severity through dyslipidemia, altered secretion of adipokines and adhesion molecules, endothelial dysfunction and the RAS. Therefore, targeting these aspects might provide new opportunities for developing novel therapeutic approaches to decrease the severity of SARS-CoV-2 infection in patients.
[1]. Kakodkar P, Kaka N, Baig MN, A comprehensive literature review on the clinical presentation, and management of the pandemic coronavirus disease 2019 (COVID-19) Cureus 2020 12(4):e756010.7759/cureus.7560 [Google Scholar] [CrossRef]
[2]. Wang L, Wang Y, Ye D, Liu Q, Review of the 2019 novel coronavirus (SARS-CoV-2) based on current evidence Int J Antimicrob Agents 2020 55(6):10594810.1016/j.ijantimicag.2020.10594832201353 [Google Scholar] [CrossRef] [PubMed]
[3]. Tu H, Tu S, Gao S, Shao A, Sheng J, Current epidemiological and clinical features of COVID-19; a global perspective from China J Infect 2020 81(1):01-09.10.1016/j.jinf.2020.04.01132315723 [Google Scholar] [CrossRef] [PubMed]
[4]. Petrakis D, Marginğ D, Tsarouhas K, Tekos F, Stan M, Nikitovic D, Obesity-A risk factor for increased COVID-19 prevalence, severity and lethality (Review) Mol Med Rep 2020 22(1):09-19.10.3892/mmr.2020.1112732377709 [Google Scholar] [CrossRef] [PubMed]
[5]. Emami A, Javanmardi F, Pirbonyeh N, Akbari A, Prevalence of underlying diseases in hospitalized patients with COVID-19: A systematic review and meta-analysis Arch Acad Emerg Med 2020 8(1):e3510.1371/journal.pone.024126533095835 [Google Scholar] [CrossRef] [PubMed]
[6]. Wu Z, McGoogan JM, Characteristics of and important lessons from the Coronavirus Disease 2019 (COVID-19) outbreak in China: Summary of a report of 72314 cases from the Chinese Center for Disease Control and Prevention JAMA 2020 323(13):1239-42.10.1001/jama.2020.264832091533 [Google Scholar] [CrossRef] [PubMed]
[7]. Li B, Yang J, Zhao F, Zhi L, Wang X, Liu L, Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China Clin Res Cardiol 2020 109(5):531-38.10.1007/s00392-020-01626-932161990 [Google Scholar] [CrossRef] [PubMed]
[8]. Aggarwal G, Cheruiyot I, Aggarwal S, Wong J, Lippi G, Lavie CJ, Association of cardiovascular disease with Coronavirus Disease 2019 (COVID-19) severity: A meta-analysis Curr Probl Cardiol 2020 45(8):10061710.1016/j.cpcardiol.2020.10061732402515 [Google Scholar] [CrossRef] [PubMed]
[9]. Popkin BM, Du S, Green WD, Beck MA, Algaith T, Herbst CH, Individuals with obesity and COVID-19: A global perspective on the epidemiology and biological relationships Obes Rev 2020 21(11):e1312810.1111/obr.1312832845580 [Google Scholar] [CrossRef] [PubMed]
[10]. Yang J, Hu J, Zhu C, Obesity aggravates COVID-19: A systematic review and meta analysis J Med Virol 2020 10.1002/jmv.2623732603481 [Google Scholar] [CrossRef] [PubMed]
[11]. Hu Y, Sun J, Dai Z, Deng H, Li X, Huang Q, Prevalence and severity of Coronavirus Disease 2019 (COVID-19): A systematic review and meta-analysis J Clin Virol 2020 127:10437110.1016/j.jcv.2020.10437132315817 [Google Scholar] [CrossRef] [PubMed]
[12]. Long B, Brady WJ, Koyfman A, Gottlieb M, Parrillo L, Formisano P, Raceti GA, Cardiovascular complications in COVID-19 Am J Emerg Med 2020 38(7):1504-07.10.1016/j.ajem.2020.04.04832317203 [Google Scholar] [CrossRef] [PubMed]
[13]. Longo M, Zatterale F, Naderi J, Parrillo L, Formisano P, Raciti GA, Adipose tissue dysfunction as determinant of obesity-associated metabolic complications Int J Mol Sci 2019 20(9):235810.3390/ijms2009235831085992 [Google Scholar] [CrossRef] [PubMed]
[14]. Cristancho AG, Lazar MA, Forming functional fat: A growing understanding of adipocyte differentiation Nat Rev Mol Cell Biol 2011 12(11):722-34.10.1038/nrm319821952300 [Google Scholar] [CrossRef] [PubMed]
[15]. Xue Y, Jiang L, Cheng Q, Chen H, Yu Y, Lin Y, Adipokines in psoriatic arthritis patients: The correlations with osteoclast precursors and bone erosions PLoS One 2012 7(10):e4674010.1371/journal.pone.004674023144698 [Google Scholar] [CrossRef] [PubMed]
[16]. Gupte M, Thatcher SE, Boustany-Kari CM, Shoemaker R, Yiannikouris F, Zhang X, Angiotensin converting enzyme 2 contributes to sex differences in the development of obesity hypertension in C57BL/6 mice Arterioscler Thromb Vasc Biol 2012 32(6):1392-99.10.1161/ATVBAHA.112.24855922460555 [Google Scholar] [CrossRef] [PubMed]
[17]. Zwick RK, Guerrero-Juarez CF, Horsley V, Plikus MV, Anatomical, physiological, and functional diversity of adipose tissue Cell Metab 2018 27(1):68-83.10.1016/j.cmet.2017.12.00229320711 [Google Scholar] [CrossRef] [PubMed]
[18]. Ryan PM, Caplice NM, Is adipose tissue a reservoir for viral spread, immune activation, and cytokine amplification in coronavirus disease 2019? Obesity (Silver Spring) 2020 28(7):1191-94.10.1002/oby.2284332314868 [Google Scholar] [CrossRef] [PubMed]
[19]. Pérez-Torres I, Gutiérrez-Alvarez Y, Guarner-Lans V, Díaz-Díaz E, Manzano Pech L, Caballero-Chacón SDC, Intra-abdominal fat adipocyte hypertrophy through a progressive alteration of lipolysis and lipogenesis in metabolic syndrome rats Nutrients 2019 11(7):152910.3390/nu1107152931284400 [Google Scholar] [CrossRef] [PubMed]
[20]. Umano GR, Pistone C, Tondina E, Moiraghi A, Lauretta D, Del Giudice EM, Pediatric obesity and the immune system Front Pediatr 2019 7:48710.3389/fped.2019.0048731824900 [Google Scholar] [CrossRef] [PubMed]
[21]. Sniderman AD, Couture P, Martin SS, De Graaf J, Lawler PR, Cromwell WC, Hypertriglyceridemia and cardiovascular risk: A cautionary note about metabolic confounding J Lipid Res 2018 59(7):1266-75.10.1194/jlr.R08227129769239 [Google Scholar] [CrossRef] [PubMed]
[22]. Hu X, Chen D, Wu L, He G, Ye W, Low serum cholesterol level among patients with COVID-19 infection in Wenzhou, China (February 21, 2020) Available at SSRN: https://ssrn.com/abstract=3544826 or http://dx.doi.org/10.2139/ssrn.354482610.2139/ssrn.3544826 [Google Scholar] [CrossRef]
[23]. Hu X, Chen D, Wu L, He G, Ye W, Declined serum high density lipoprotein cholesterol is associated with the severity of COVID-19 infection Clin Chim Acta 2020 510:105-10.10.1016/j.cca.2020.07.01532653486 [Google Scholar] [CrossRef] [PubMed]
[24]. Hussain A, Vasas P, El-Hasani S, Letter to the Editor: Obesity as a risk factor for greater severity of COVID-19 in patients with metabolic associated fatty liver disease Metabolism 2020 108:15425610.1016/j.metabol.2020.15425632360211 [Google Scholar] [CrossRef] [PubMed]
[25]. Wei X, Zeng W, Su J, Wan H, Yu X, Cao X, Hypolipidemia is associated with the severity of COVID-19 J Clin Lipidol 2020 14(3):297-304.10.1016/j.jacl.2020.04.00832430154 [Google Scholar] [CrossRef] [PubMed]
[26]. Bojkova D, Klann K, Koch B, Widera M, Krause D, Ciesek S, Proteomics of SARS-CoV-2-infected host cells reveals therapy targets Nature 2020 583(7816):469-72.10.1038/s41586-020-2332-732408336 [Google Scholar] [CrossRef] [PubMed]
[27]. Cao X, Yin R, Albrecht H, Fan D, Tan W, Cholesterol: A new game player accelerating vasculopathy caused by SARS-CoV-2? Am J Physiol Endocrinol Metab 2020 319(1):E197-202.10.1152/ajpendo.00255.202032501731 [Google Scholar] [CrossRef] [PubMed]
[28]. Tien PC, Hepatitis C virus-associated alterations in lipid and lipoprotein levels: helpful or harmful to the heart? Clin Infect Dis 2017 65(4):566-67.10.1093/cid/cix36028444147 [Google Scholar] [CrossRef] [PubMed]
[29]. Meher G, Bhattacharjya S, Chakraborty H, Membrane cholesterol modulates oligomeric status and peptide-membrane interaction of severe acute respiratory syndrome coronavirus fusion peptide J Phys Chem B 2019 123(50):10654-62.10.1021/acs.jpcb.9b0845531743644 [Google Scholar] [CrossRef] [PubMed]
[30]. Shrestha SK, Statin drug therapy may increase COVID-19 infection Nepalese Medical Journal 2020 3(1):326-27.10.3126/nmj.v3i1.28256 [Google Scholar] [CrossRef]
[31]. Subir R, Pros and cons for use of statins in people with coronavirus disease-19 (COVID-19) Diabetes Metab Syndr 2020 14(5):1225-29.10.1016/j.dsx.2020.07.01132683320 [Google Scholar] [CrossRef] [PubMed]
[32]. Bansal M, Cardiovascular disease and COVID-19 Diabetes Metab Syndr 2020 14(3):247-50.10.1016/j.dsx.2020.03.01332247212 [Google Scholar] [CrossRef] [PubMed]
[33]. Rychter AM, Zawada A, Ratajczak AE, Dobrowolska A, Krela-Kaźmierczak I, Should patients with obesity be more afraid of COVID-19? Obes Rev 2020 10.1111/obr.1308332583537 [Google Scholar] [CrossRef] [PubMed]
[34]. Dutheil F, Gordon BA, Naughton G, Crendal E, Courteix D, Chaplais E, Cardiovascular risk of adipokines: A review J Int Med Res 2018 46(6):2082-95.10.1177/030006051770657828974138 [Google Scholar] [CrossRef] [PubMed]
[35]. Landecho MF, Tuero C, Valentí V, Bilbao I, de la Higuera M, Frühbeck G, Relevance of leptin and other adipokines in obesity-associated cardiovascular risk Nutrients 2019 11(11):266410.3390/nu1111266431694146 [Google Scholar] [CrossRef] [PubMed]
[36]. Post A, Bakker SJL, Dullaart RPF, Obesity, adipokines and COVID-19 Eur J Clin Invest 2020 2020:e1331310.1111/eci.1331332531806 [Google Scholar] [CrossRef] [PubMed]
[37]. Woodward L, Akoumianakis I, Antoniades C, Unravelling the adiponectin paradox: novel roles of adiponectin in the regulation of cardiovascular disease Br J Pharmacol 2017 174(22):4007-20.10.1111/bph.1361927629236 [Google Scholar] [CrossRef] [PubMed]
[38]. Katsiki N, Mikhailidis DP, Banach M, Leptin, cardiovascular diseases and type 2 diabetes mellitus Acta Pharmacol Sin 2018 39(7):1176-88.10.1038/aps.2018.4029877321 [Google Scholar] [CrossRef] [PubMed]
[39]. Finucane FM, Luan J, Wareham NJ, Sharp SJ, O’Rahlly S, Balkau B, Correlation of the leptin: Adiponectin ratio with measures of insulin resistance in non-diabetic individuals Diabetologia 2009 52(11):2345-49.10.1007/s00125-009-1508-319756488 [Google Scholar] [CrossRef] [PubMed]
[40]. Malavazos AE, Romanelli MMC, Bandera F, Iacobellis G, Targeting the adipose tissue in COVID-19 Obesity (Silver Spring) 2020 28(7):1178-79.10.1002/oby.2284432314871 [Google Scholar] [CrossRef] [PubMed]
[41]. Demerath E, Towne B, Blangero J, Siervogel RM, The relationship of soluble ICAM-1, VCAM-1, P-selectin and E-selectin to cardiovascular disease risk factors in healthy men and women Ann Hum Biol 2001 28(6):664-78.10.1080/0301446011004853011726042 [Google Scholar] [CrossRef] [PubMed]
[42]. Gerhardt T, Ley K, Monocyte trafficking across the vessel wall Cardiovasc Res 2015 107(3):321-30.10.1093/cvr/cvv14725990461 [Google Scholar] [CrossRef] [PubMed]
[43]. Kosmas CE, Silverio D, Sourlas A, Montan PD, Guzman E, Garcia MJ, Anti-inflammatory therapy for cardiovascular disease Ann Transl Med 2019 7(7):14710.21037/atm.2019.02.3431157268 [Google Scholar] [CrossRef] [PubMed]
[44]. Ruiz-Canela M, Bes-Rastrollo M, Martínez-González MA, The role of dietary inflammatory index in cardiovascular disease, metabolic syndrome and mortality Int J Mol Sci 2016 17(8):126510.3390/ijms1708126527527152 [Google Scholar] [CrossRef] [PubMed]
[45]. Kotwal GJ, Chien S, Macrophage differentiation in normal and accelerated wound healing Results Probl Cell Differ 2017 62:353-64.10.1007/978-3-319-54090-0_1428455716 [Google Scholar] [CrossRef] [PubMed]
[46]. Korakas E, Ikonomidis I, Kousathana F, Balampanis K, Kountouri A, Raptis A, Obesity and COVID-19: Immune and metabolic derangement as a possible link to adverse clinical outcomes Am J Physiol Endocrinol Metab 2020 319(1):E105-09.10.1152/ajpendo.00198.202032459524 [Google Scholar] [CrossRef] [PubMed]
[47]. Kitamoto S, Egashira K, Anti-monocyte chemoattractant protein-1 gene therapy for cardiovascular diseases Expert Rev Cardiovasc Ther 2003 1(3):393-400.10.1586/14779072.1.3.39315030267 [Google Scholar] [CrossRef] [PubMed]
[48]. Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y, Novel modulator for endothelial adhesion molecules: Adipocyte-derived plasma protein adiponectin Circulation 1999 100(25):2473-76.10.1161/01.CIR.100.25.247310604883 [Google Scholar] [CrossRef] [PubMed]
[49]. Skilton MR, Nakhla S, Sieveking DP, Caterson ID, Celermajer DS, Pathophysiological levels of the obesity related peptides resistin and ghrelin increase adhesion molecule expression on human vascular endothelial cells Clin Exp Pharmacol Physiol 2005 32(10):839-44.10.1111/j.1440-1681.2005.04274.x16173945 [Google Scholar] [CrossRef] [PubMed]
[50]. O’Dea KP, Young AJ, Yamamoto H, Robotham JL, Brennan FM, Takata M, Lung-marginated monocytes modulate pulmonary microvascular injury during early endotoxemia Am J Respir Crit Care Med 2005 172(9):1119-27.10.1164/rccm.200504-605OC16081546 [Google Scholar] [CrossRef] [PubMed]
[51]. Herold S, von Wulffen W, Steinmueller M, Pleschka S, Kuziel WA, Mack M, Alveolar epithelial cells direct monocyte transepithelial migration upon influenza virus infection: Impact of chemokines and adhesion molecules J Immunol 2006 177(3):1817-24.10.4049/jimmunol.177.3.181716849492 [Google Scholar] [CrossRef] [PubMed]
[52]. Tong M, Jiang Y, Xia D, Xiong Y, Zheng Q, Chen F, Elevated serum endothelial cell adhesion molecules expression in COVID-19 patients J Infect Dis 2020 (6):894-98.10.1093/infdis/jiaa34932582936 [Google Scholar] [CrossRef] [PubMed]
[53]. Miller AJ, Arnold AC, The renin-angiotensin system in cardiovascular autonomic control: Recent developments and clinical implications Clin Auton Res 2019 29(2):231-43.10.1007/s10286-018-0572-530413906 [Google Scholar] [CrossRef] [PubMed]
[54]. Mönkemüller K, Fry L, Rickes S, COVID-19, coronavirus, SARS-CoV-2 and the small bowel Rev Esp Enferm Dig 2020 112(5):383-88.10.17235/reed.2020.7137/202032343593 [Google Scholar] [CrossRef] [PubMed]
[55]. Lu H, Cassis LA, Kooi CW, Daugherty A, Wu C, Charnigo R, Structure and functions of angiotensinogen Hypertens Res 2016 39(7):492-500.10.1038/hr.2016.1726888118 [Google Scholar] [CrossRef] [PubMed]
[56]. Ito M, Oliverio MI, Mannon PJ, Best CF, Maeda N, Smithies O, Regulation of blood pressure by the type 1A angiotensin II receptor gene Proc Natl Acad Sci USA 1995 92(8):3521-25.10.1073/pnas.92.8.35217724593 [Google Scholar] [CrossRef] [PubMed]
[57]. Oliverio MI, Best CF, Kim HS, Arendshorst WJ, Smithies O, Coffman TM, Angiotensin II responses in AT1A receptor-deficient mice: A role for AT1B receptors in blood pressure regulation Am J Physiol 1997 272(4 Pt 2):F515-20.10.1152/ajprenal.1997.272.4.F5159140053 [Google Scholar] [CrossRef] [PubMed]
[58]. Lu H, Balakrishnan A, Howatt DA, Wu C, Charnigo R, Liau G, Comparative effects of different modes of renin angiotensin system inhibition on hypercholesterolaemia-induced atherosclerosis Br J Pharmacol 2012 165(6):2000-08.10.1111/j.1476-5381.2011.01712.x22014125 [Google Scholar] [CrossRef] [PubMed]
[59]. Unger T, The role of the renin-angiotensin system in the development of cardiovascular disease Am J Cardiol 2002 89(2A):3A-10A.10.1016/S0002-9149(01)02321-9 [Google Scholar] [CrossRef]
[60]. Wen Z, Mai Z, Chen Y, Wang J, Geng D, Angiotensin II receptor blocker reverses heart failure by attenuating local oxidative stress and preserving resident stem cells in rats with myocardial infarction Am J Transl Res 2018 10(8):2387-401. [Google Scholar]
[61]. Yousif MHM, Benter IF, Diz DI, Chappell MC, Angiotensin-(1-7)-dependent vasorelaxation of the renal artery exhibits unique angiotensin and bradykinin receptor selectivity Peptides 2017 90:10-16.10.1016/j.peptides.2017.02.00128192151 [Google Scholar] [CrossRef] [PubMed]
[62]. Siltari A, Korpela R, Vapaatalo H, Bradykinin -induced vasodilatation: Role of age, ACE1-inhibitory peptide, mas- and bradykinin receptors Peptides 2016 85:46-55.10.1016/j.peptides.2016.09.00127628189 [Google Scholar] [CrossRef] [PubMed]
[63]. Cassis LA, Police SB, Yiannikouris F, Thatcher SE, Local adipose tissue renin-angiotensin system Curr Hypertens Rep 2008 10(2):93-98.10.1007/s11906-008-0019-918474174 [Google Scholar] [CrossRef] [PubMed]