{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T12:39:44Z","timestamp":1768912784477,"version":"3.49.0"},"reference-count":68,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T00:00:00Z","timestamp":1677024000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Background and Aim. Degenerative Aortic Stenosis (DAS) is a common disease that causes substantial morbidity and mortality worldwide, especially in the older population. Our aim was to further investigate novel serum and tissue biomarkers to elucidate biological processes involved in this entity. Material and Methods. We evaluated the expression of six biomarkers significantly involved in cardiovascular pathology, i.e., irisin, periostin, osteoglycin, interleukin 18, high mobility group box 1 and proprotein convertase subtilisin\/kexin type 9 in the serum at the protein level, and in the tissue at both the protein and mRNA levels of patients with AS (N = 60). Five normal valves obtained after transplantation from hearts of patients with idiopathic dilated cardiomyopathy were also studied. Serum measurements were also performed in 22 individuals without valvular disease who served as controls (C). Results. Higher levels of all factors were found in DAS patients\u2019 serum than in normal C. IHC and PCR mRNA tissue analysis showed the presence of all biomarkers in the aortic valve cusps with DAS, but no trace of PCR mRNA was found in the five transplantation valves. Moreover, periostin serum levels correlated significantly with IHC and mRNA tissue levels in AS patients. Conclusion. We showed that six widely prevalent biomarkers affecting the atherosclerotic process were also involved in DAS, suggesting a strong osteogenic and pro-inflammatory profile, indicating that aortic valve calcification is a multifactorial biological process.<\/jats:p>","DOI":"10.3390\/biology12030347","type":"journal-article","created":{"date-parts":[[2023,2,22]],"date-time":"2023-02-22T05:01:32Z","timestamp":1677042092000},"page":"347","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Tissue and Serum Biomarkers in Degenerative Aortic Stenosis-Insights into Pathogenesis, Prevention and Therapy"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7637-8152","authenticated-orcid":false,"given":"Alkistis","family":"Kapelouzou","sequence":"first","affiliation":[{"name":"Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1227-5274","authenticated-orcid":false,"given":"Styliani","family":"Geronikolou","sequence":"additional","affiliation":[{"name":"Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irene","family":"Lidoriki","sequence":"additional","affiliation":[{"name":"1st Department of Surgery, School of Medicine, National and Kapodistrian University of Athens, Laiko Hospital, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christos","family":"Kontogiannis","sequence":"additional","affiliation":[{"name":"Department of Clinical Therapeutics, National and Kapodistrian University of Athens Alexandra Hospital, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Loukas","family":"Kaklamanis","sequence":"additional","affiliation":[{"name":"Department of Pathology, Onassis Cardiac Surgery Center, 17674 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Loukas","family":"Tsourelis","sequence":"additional","affiliation":[{"name":"Department of Pathology, Onassis Cardiac Surgery Center, 17674 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dennis V.","family":"Cokkinos","sequence":"additional","affiliation":[{"name":"Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"744","DOI":"10.1056\/NEJMra1313875","article-title":"Aortic-Valve Stenosis\u2014From Patients at Risk to Severe Valve Obstruction","volume":"371","author":"Otto","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.amcp.2018.10.004","article-title":"Position papier franc\u0327ais (GACI) pour l\u2019implantation de valve aortique percutan\u00e9e (TAVI)","volume":"2018","author":"Benamer","year":"2018","journal-title":"Arch. Mal. Coeur Vaiss. Prat."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/S0140-6736(06)69208-8","article-title":"Burden of valvular heart diseases: A population-based study","volume":"368","author":"Nkomo","year":"2006","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1136\/heart.89.9.1019","article-title":"Cardiovascular risk factors in patients with aortic stenosis predict prevalence of coronary artery disease but not of aortic stenosis: An angiographic pair matched case-control study","volume":"89","author":"Ortlepp","year":"2003","journal-title":"Heart"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"49","DOI":"10.5339\/gcsp.2015.49","article-title":"Serum and tissue biomarkers in aortic stenosis","volume":"2015","author":"Kapelouzou","year":"2015","journal-title":"Glob. Cardiol. Sci. Pract."},{"key":"ref_6","first-page":"483","article-title":"Aortic valve stenosis: An active atheroinflammatory process","volume":"18","author":"Helske","year":"2007","journal-title":"Curr. Opin. Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.cyto.2019.01.009","article-title":"Differential expression patterns of Toll Like Receptors and Interleukin-37 between calcific aortic and mitral valve cusps in humans","volume":"116","author":"Kapelouzou","year":"2019","journal-title":"Cytokine"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.atherosclerosis.2020.02.016","article-title":"Innate and adaptive immunity in cardiovascular calcification","volume":"306","author":"Passos","year":"2020","journal-title":"Atherosclerosis"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.peptides.2013.11.024","article-title":"Cardiac, skeletal muscle and serum irisin responses to with or without water exercise in young and old male rats: Cardiac muscle produces more irisin than skeletal muscle","volume":"52","author":"Aydin","year":"2014","journal-title":"Peptides"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Silvestrini, A., Bruno, C., Vergani, E., Venuti, A., Favuzzi, A.M.R., Guidi, F., Nicolotti, N., Meucci, E., Mordente, A., and Mancini, A. (2019). Circulating irisin levels in heart failure with preserved or reduced ejection fraction: A pilot study. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0210320"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"615","DOI":"10.1159\/000477867","article-title":"Serum Irisin Predicts Mortality Risk in Acute Heart Failure Patients","volume":"42","author":"Shen","year":"2017","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"888","DOI":"10.1016\/j.amjmed.2014.04.025","article-title":"Serum Irisin Levels, Precocious Myocardial Infarction, and Healthy Exceptional Longevity","volume":"127","author":"Emanuele","year":"2014","journal-title":"Am. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.peptides.2014.02.008","article-title":"Irisin: A potentially candidate marker for myocardial infarction","volume":"55","author":"Kuloglu","year":"2014","journal-title":"Peptides"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"44","DOI":"10.4070\/kcj.2016.0079","article-title":"Serum Irisin Level Can Predict the Severity of Coronary Artery Disease in Patients with Stable Angina","volume":"47","author":"Efe","year":"2017","journal-title":"Korean Circ. J."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Zhao, Y.T., Wang, H., Zhang, S., Du, J., Zhuang, S., and Zhao, T.C. (2016). Irisin Ameliorates Hypoxia\/Reoxygenation-Induced Injury through Modulation of Histone Deacetylase 4. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0166182"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"18732","DOI":"10.1038\/srep18732","article-title":"Irisin promotes osteoblast proliferation and differentiation via activating the MAP kinase signaling pathways","volume":"6","author":"Qiao","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1756","DOI":"10.1016\/j.cell.2018.10.025","article-title":"Irisin mediates effects on bone and fat via \u03b1V Integrin receptors","volume":"175","author":"Kim","year":"2018","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1111\/nyas.13345","article-title":"Irisin and musculoskeletal health","volume":"1402","author":"Colaianni","year":"2017","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2292","DOI":"10.1172\/JCI40973","article-title":"Periostin advances atherosclerotic and rheumatic cardiac valve degeneration by inducing angiogenesis and MMP production in humans and rodents","volume":"120","author":"Hakuno","year":"2010","journal-title":"J. Clin. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.jjcc.2013.09.013","article-title":"Periostin expression is upregulated and associated with myocardial fibrosis in human failing hearts","volume":"63","author":"Zhao","year":"2014","journal-title":"J. Cardiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1161\/CIRCRESAHA.107.149047","article-title":"Genetic manipulation of periostin expression reveals a role in cardiac hypertrophy and ventricular remodeling","volume":"101","author":"Oka","year":"2007","journal-title":"Circ. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1916","DOI":"10.1016\/j.athoracsur.2009.07.038","article-title":"Periostin Is a Novel Factor in Cardiac Remodeling After Experimental and Clinical Unloading of the Failing Heart","volume":"88","author":"Stansfield","year":"2009","journal-title":"Ann. Thorac. Surg."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1690421","DOI":"10.1155\/2021\/1690421","article-title":"Circulating Levels of IL-13, TGF-\u03b21, and Periostin as Potential Biomarker for Coronary Artery Disease with Acute Heart Failure","volume":"2021","author":"Qiu","year":"2021","journal-title":"Evid. Based Complement. Altern. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.matbio.2017.09.002","article-title":"Osteoglycin prevents the development of age-related diastolic dysfunction during pressure overload by reducing cardiac fibrosis and inflammation","volume":"66","author":"Deckx","year":"2018","journal-title":"Matrix Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1161\/CIRCRESAHA.116.304599","article-title":"Osteoglycin prevents cardiac dilatation and dysfunction after myocardial infarction through infarct collagen strengthening","volume":"116","author":"Voss","year":"2015","journal-title":"Circ. Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1093\/cvr\/cvy035","article-title":"Osteoglycin attenuates cardiac fibrosis by suppressing cardiac myofibroblast proliferation and migration through antagonizing lysophosphatidic acid 3\/matrix metalloproteinase 2\/epidermal growth factor receptor signalling","volume":"114","author":"Zuo","year":"2018","journal-title":"Cardiovasc. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1161\/ATVBAHA.114.303486","article-title":"Circulating Osteoglycin and NGAL\/MMP9 Complex Concentrations Predict 1-Year Major Adverse Cardiovascular Events after Coronary Angiography","volume":"34","author":"Cheng","year":"2014","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"11616","DOI":"10.1074\/jbc.M111.292193","article-title":"Role of Osteoglycin in the Linkage between Muscle and Bone","volume":"287","author":"Tanaka","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1097\/SHK.0b013e318160f215","article-title":"Interleukin 18 in the heart","volume":"30","author":"Wang","year":"2008","journal-title":"Shock"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.ijcard.2009.01.022","article-title":"Increased interleukin-18 expression in nonrheumatic aortic valve stenosis","volume":"144","author":"Naito","year":"2010","journal-title":"Int. J. Cardiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"998","DOI":"10.1016\/j.ijcard.2016.07.036","article-title":"Interleukin 18 promotes myofibroblast activation of valvular interstitial cells","volume":"221","author":"Zhou","year":"2016","journal-title":"Int. J. Cardiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"H76","DOI":"10.1152\/ajpheart.01285.2008","article-title":"IL-18 induction of osteopontin mediates cardiac fibrosis and diastolic dysfunction in mice","volume":"297","author":"Yu","year":"2009","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/j.atherosclerosis.2011.03.015","article-title":"Interleukin 18 and coronary heart disease: Prospective study and systematic review","volume":"217","author":"Jefferis","year":"2011","journal-title":"Atherosclerosis"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2530","DOI":"10.3892\/mmr.2017.6287","article-title":"High mobility group box 1 induces calcification of aortic valve interstitial cells via toll-like receptor 4","volume":"15","author":"Shen","year":"2017","journal-title":"Mol. Med. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.jtcvs.2015.09.077","article-title":"High-mobility group box-1 protein induces osteogenic phenotype changes in aortic valve interstitial cells","volume":"151","author":"Wang","year":"2016","journal-title":"J. Thorac. Cardiovasc. Surg."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.cca.2009.06.016","article-title":"Increased serum HMGB1 is related to the severity of coronary artery stenosis","volume":"406","author":"Hu","year":"2009","journal-title":"Clin. Chim. Acta"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1016\/j.atherosclerosis.2016.03.010","article-title":"PCSK9 in relation to coronary plaque inflammation: Results of the ATHEROREMO-IVUS study","volume":"248","author":"Cheng","year":"2016","journal-title":"Atherosclerosis"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ijcard.2022.01.014","article-title":"Associations of pro-protein convertase subtilisin-like kexin type 9, soluble low-density lipoprotein receptor and coronary artery disease: A case-control study","volume":"350","author":"Peng","year":"2022","journal-title":"Int. J. Cardiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1002\/jca.21317","article-title":"Genetic and biochemical analyses in dyslipidemic patients undergoing LDL apheresis","volume":"29","author":"Donato","year":"2014","journal-title":"J. Clin. Apher."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1403","DOI":"10.2174\/0929867324666170303123734","article-title":"Treatment with Proprotein Convertase Subtilisin\/Kexin Type 9 (PCSK9) Inhibitors to Reduce Cardiovascular Inflammation and Outcomes","volume":"24","author":"Liberale","year":"2017","journal-title":"Curr. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"427","DOI":"10.2174\/1381612824666171227215708","article-title":"Effects of High Intensity Statin Therapy in the Treatment of Diabetic Dyslipidemia in Patients with Coronary Artery Disease","volume":"24","author":"Vavlukis","year":"2018","journal-title":"Curr. Pharm. Des."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1177\/0300060516648030","article-title":"Proprotein convertase subtilisin\/kexin type 9 levels and aortic valve calcification: A prospective, cross sectional study","volume":"44","author":"Wang","year":"2016","journal-title":"J. Int. Med. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3225","DOI":"10.1016\/j.jacc.2018.09.063","article-title":"PCSK9 Involvement in Aortic Valve Calcification","volume":"72","author":"Poggio","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1016\/j.jacc.2018.04.064","article-title":"Hemodynamic Deterioration of Surgically Implanted Bioprosthetic Aortic Valves","volume":"72","author":"Salaun","year":"2018","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1903","DOI":"10.1007\/s00018-012-0977-6","article-title":"PCSK9 regulates neuronal apoptosis by adjusting ApoER2 levels and signaling","volume":"69","author":"Kysenius","year":"2012","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/0003-2697(87)90021-2","article-title":"Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction","volume":"162","author":"Chomczynski","year":"1987","journal-title":"Anal. Biochem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/j.amjcard.2004.05.055","article-title":"Relation of N-Terminal Pro\u2013B-Type Natriuretic Peptide to Severity of Valvular Aortic Stenosis","volume":"94","author":"Weber","year":"2004","journal-title":"Am. J. Cardiol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2067","DOI":"10.1136\/heartjnl-2017-312304","article-title":"Timing of intervention in aortic stenosis: A review of current and future strategies","volume":"104","author":"Everett","year":"2018","journal-title":"Heart"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1161\/CIRCULATIONAHA.111.051052","article-title":"Assessment of Valvular Calcification and Inflammation by Positron Emission Tomography in Patients with Aortic Stenosis","volume":"125","author":"Dweck","year":"2012","journal-title":"Circulation"},{"key":"ref_50","first-page":"XC10","article-title":"Comparison of Polymerase Chain Reaction and Immunohistochemistry Assays for Analysing Human Papillomavirus Infection in Oral Squamous Cell Carcinoma","volume":"11","author":"Awan","year":"2017","journal-title":"J. Clin. Diagn. Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1001\/jamacardio.2020.0728","article-title":"An Exploratory Analysis of Proprotein Convertase Subtilisin\/Kexin Type 9 Inhibition and Aortic Stenosis in the FOURIER Trial","volume":"5","author":"Bergmark","year":"2020","journal-title":"JAMA Cardiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2389","DOI":"10.1056\/NEJMoa043876","article-title":"A Randomized Trial of Intensive Lipid-Lowering Therapy in Calcific Aortic Stenosis","volume":"352","author":"Cowell","year":"2005","journal-title":"N. Engl. J. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1343","DOI":"10.1056\/NEJMoa0804602","article-title":"Intensive Lipid Lowering with Simvastatin and Ezetimibe in Aortic Stenosis","volume":"359","author":"Pedersen","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1016\/j.jacc.2006.07.072","article-title":"Rosuvastatin affecting aortic valve endothelium to slow the progression of aortic stenosis","volume":"49","author":"Moura","year":"2007","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1161\/CIRCULATIONAHA.109.900027","article-title":"Effect of Lipid lowering with rosuvastatin on progression of aortic stenosis: Results of the aortic stenosis progression observation: Measuring effects of rosuvastatin (ASTRONOMER) trial","volume":"121","author":"Chan","year":"2010","journal-title":"Circulation"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/j.acvd.2019.06.003","article-title":"Proprotein convertase subtilisin\/kexin type 9 inhibitors: New insights into cardiovascular atherosclerotic pathophysiology with therapeutic implications","volume":"112","author":"Cokkinos","year":"2019","journal-title":"Arch. Cardiovasc. Dis."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.atherosclerosis.2015.05.021","article-title":"Statins and the coronary plaque calcium \u201cparadox\u201d: Insights from non-invasive and invasive imaging","volume":"241","author":"Ferencik","year":"2015","journal-title":"Atherosclerosis"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/j.jacbts.2020.05.004","article-title":"Genetic and In Vitro Inhibition of PCSK9 and Calcific Aortic Valve Stenosis","volume":"5","author":"Perrot","year":"2020","journal-title":"JACC Basic Transl. Sci."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Sundararaman, S.S., D\u00f6ring, Y., and van Der Vorst, E.P. (2021). PCSK9: A multi-faceted protein that is involved in cardiovascular biology. Biomedicines, 9.","DOI":"10.3390\/biomedicines9070793"},{"key":"ref_60","first-page":"934","article-title":"Pathogenetic mechanism of senile calcific aortic stenosis: The role of apoptosis","volume":"111","author":"Lee","year":"1998","journal-title":"Chin. Med. J."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e023328","DOI":"10.1161\/JAHA.121.023328","article-title":"Effects of PCSK9 Targeting: Alleviating Oxidation, Inflammation, and Atherosclerosis","volume":"11","author":"Punch","year":"2022","journal-title":"J. Am. Heart Assoc."},{"key":"ref_62","first-page":"384","article-title":"Empagliflozin alleviates renal inflammation and oxidative stress in streptozotocin-induced diabetic rats partly by repressing HMGB1-TLR4 receptor axis","volume":"22","author":"Jigheh","year":"2019","journal-title":"Iran. J. Basic Med. Sci."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"109825","DOI":"10.1016\/j.cellsig.2020.109825","article-title":"The SGLT2 inhibitor Empagliflozin attenuates interleukin-17A-induced human aortic smooth muscle cell proliferation and migration by targeting TRAF3IP2\/ROS\/NLRP3\/Caspase-1-dependent IL-1\u03b2 and IL-18 secretion","volume":"77","author":"Sukhanov","year":"2021","journal-title":"Cell. Signal."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"569.4","DOI":"10.1096\/fasebj.2018.32.1_supplement.569.4","article-title":"Administration of SGLT2 inhibitor empagliflozin against TNF-\u03b1 induced endothelial dysfunction in human venous and arterial endothelial cells","volume":"32","author":"Uthman","year":"2018","journal-title":"FASEB J."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Pirklbauer, M., Sallaberger, S., Staudinger, P., Corazza, U., Leierer, J., Mayer, G., and Schramek, H. (2021). Empagliflozin Inhibits IL-1\u03b2-Mediated Inflammatory Response in Human Proximal Tubular Cells. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22105089"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Tsai, K.-F., Chen, Y.-L., Chiou, T., Chu, T.-H., Li, L.-C., Ng, H.-Y., Lee, W.-C., and Lee, C.-T. (2021). Emergence of SGLT2 Inhibitors as Powerful Antioxidants in Human Diseases. Antioxidants, 10.","DOI":"10.3390\/antiox10081166"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/S0735-1097(99)00584-7","article-title":"Observed and relative survival after aortic valve replacement","volume":"35","author":"Kvidal","year":"2000","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S0021-9150(01)00617-7","article-title":"Nonobstructive aortic valve calcification: A window to significant coronary artery disease","volume":"161","author":"Adler","year":"2002","journal-title":"Atherosclerosis"}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/12\/3\/347\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:39:06Z","timestamp":1760121546000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/12\/3\/347"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,22]]},"references-count":68,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["biology12030347"],"URL":"https:\/\/doi.org\/10.3390\/biology12030347","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,22]]}}}