{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,21]],"date-time":"2026-02-21T03:56:54Z","timestamp":1771646214105,"version":"3.50.1"},"reference-count":41,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T00:00:00Z","timestamp":1634169600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Austria-Hungary Action Foundation","award":["92\u00f6u8"],"award-info":[{"award-number":["92\u00f6u8"]}]},{"DOI":"10.13039\/501100016168","name":"Ludwig Boltzmann Society","doi-asserted-by":"publisher","award":["REM2017-20"],"award-info":[{"award-number":["REM2017-20"]}],"id":[{"id":"10.13039\/501100016168","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Research, Development and Innovation Fund of Hungary","award":["2020-4.1.1-TKP2020"],"award-info":[{"award-number":["2020-4.1.1-TKP2020"]}]},{"name":"National Research, Development and Innovation Fund of Hungary","award":["FK 128809"],"award-info":[{"award-number":["FK 128809"]}]},{"name":"National Research, Development and Innovation Fund of Hungary","award":["K 132623"],"award-info":[{"award-number":["K 132623"]}]},{"name":"European Union and the European Regional Development Fund","award":["GINOP-2.3.2-15-2016-00043"],"award-info":[{"award-number":["GINOP-2.3.2-15-2016-00043"]}]},{"name":"COST Action EU-CARDIOPROTECTION","award":["CA16225"],"award-info":[{"award-number":["CA16225"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Post-ischemic left ventricular (LV) remodeling and its hypothetical prevention by repeated remote ischemic conditioning (rRIC) in male Sprague\u2013Dawley rats were studied. Myocardial infarction (MI) was evoked by permanent ligation of the left anterior descending coronary artery (LAD), and myocardial characteristics were tested in the infarcted anterior and non-infarcted inferior LV regions four and\/or six weeks later. rRIC was induced by three cycles of five-minute-long unilateral hind limb ischemia and five minutes of reperfusion on a daily basis for a period of two weeks starting four weeks after LAD occlusion. Sham operated animals served as controls. Echocardiographic examinations and invasive hemodynamic measurements revealed distinct changes in LV systolic function between four and six weeks after MI induction in the absence of rRIC (i.e., LV ejection fraction (LVEF) decreased from 52.8 \u00b1 2.1% to 50 \u00b1 1.6%, mean \u00b1 SEM, p &lt; 0.05) and in the presence of rRIC (i.e., LVEF increased from 48.2 \u00b1 4.8% to 55.2 \u00b1 4.1%, p &lt; 0.05). Angiotensin-converting enzyme (ACE) activity was about five times higher in the anterior LV wall at six weeks than that in sham animals. Angiotensin-converting enzyme 2 (ACE2) activity roughly doubled in post-ischemic LVs. These increases in ACE and ACE2 activities were effectively mitigated by rRIC. Ca2+-sensitivities of force production (pCa50) of LV permeabilized cardiomyocytes were increased at six weeks after MI induction together with hypophosphorylation of 1) cardiac troponin I (cTnI) in both LV regions, and 2) cardiac myosin-binding protein C (cMyBP-C) in the anterior wall. rRIC normalized pCa50, cTnI and cMyBP-C phosphorylations. Taken together, post-ischemic LV remodeling involves region-specific alterations in ACE and ACE2 activities together with changes in cardiomyocyte myofilament protein phosphorylation and function. rRIC has the potential to prevent these alterations and to improve LV performance following MI.<\/jats:p>","DOI":"10.3390\/ijms222011064","type":"journal-article","created":{"date-parts":[[2021,10,14]],"date-time":"2021-10-14T09:10:49Z","timestamp":1634202649000},"page":"11064","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Alterations in ACE and ACE2 Activities and Cardiomyocyte Signaling Underlie Improved Myocardial Function in a Rat Model of Repeated Remote Ischemic Conditioning"],"prefix":"10.3390","volume":"22","author":[{"given":"Be\u00e1ta","family":"B\u00f3di","sequence":"first","affiliation":[{"name":"Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6149-8736","authenticated-orcid":false,"given":"Patrick M.","family":"Pilz","sequence":"additional","affiliation":[{"name":"Center for Biomedical Research, Ludwig Boltzmann Institute for Cardiovascular Research, Medical University Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lilla","family":"M\u00e1rtha","sequence":"additional","affiliation":[{"name":"Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miriam","family":"Lang","sequence":"additional","affiliation":[{"name":"Center for Biomedical Research, Ludwig Boltzmann Institute for Cardiovascular Research, Medical University Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ouafa","family":"Hamza","sequence":"additional","affiliation":[{"name":"Center for Biomedical Research, Ludwig Boltzmann Institute for Cardiovascular Research, Medical University Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3262-884X","authenticated-orcid":false,"given":"Mikl\u00f3s","family":"Fagyas","sequence":"additional","affiliation":[{"name":"Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5465-8391","authenticated-orcid":false,"given":"Petra L.","family":"Szab\u00f3","sequence":"additional","affiliation":[{"name":"Center for Biomedical Research, Ludwig Boltzmann Institute for Cardiovascular Research, Medical University Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6337-0058","authenticated-orcid":false,"given":"Dietmar","family":"Abraham","sequence":"additional","affiliation":[{"name":"Center for Anatomy and Cell Biology, Medical University Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6503-3653","authenticated-orcid":false,"given":"Attila","family":"T\u00f3th","sequence":"additional","affiliation":[{"name":"Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"},{"name":"HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian Academy of Sciences, 4032 Debrecen, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4641-7202","authenticated-orcid":false,"given":"Bruno K.","family":"Podesser","sequence":"additional","affiliation":[{"name":"Center for Biomedical Research, Ludwig Boltzmann Institute for Cardiovascular Research, Medical University Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4652-1998","authenticated-orcid":false,"given":"Attila","family":"Kiss","sequence":"additional","affiliation":[{"name":"Center for Biomedical Research, Ludwig Boltzmann Institute for Cardiovascular Research, Medical University Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4675-1542","authenticated-orcid":false,"given":"Zolt\u00e1n","family":"Papp","sequence":"additional","affiliation":[{"name":"Division of Clinical Physiology, Department of Cardiology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary"},{"name":"HAS-UD Vascular Biology and Myocardial Pathophysiology Research Group, Hungarian 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proteins","volume":"57","author":"Velden","year":"2003","journal-title":"Cardiovasc. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.yjmcc.2019.02.017","article-title":"Myofilament Ca2+ sensitivity correlates with left ventricular contractility during the progression of pressure overload-induced left ventricular myocardial hypertrophy in rats","volume":"129","author":"Ruppert","year":"2019","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1161\/01.CIR.0000155257.33485.6D","article-title":"Cardiomyocyte Stiffness in Diastolic Heart Failure","volume":"111","author":"Papp","year":"2005","journal-title":"Circulation"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.jacc.2014.10.031","article-title":"Remote ischemic conditioning","volume":"65","author":"Heusch","year":"2015","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1007\/s00424-017-1936-8","article-title":"Cardioprotection by remote ischemic conditioning and its signal transduction","volume":"469","author":"Kleinbongard","year":"2017","journal-title":"Pflug. Arch. Eur. J. Phy."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1415","DOI":"10.1016\/S0140-6736(19)32039-2","article-title":"Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2\/ERIC-PPCI): A single-blind randomised controlled trial","volume":"394","author":"Hausenloy","year":"2019","journal-title":"Lancet"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.ijcard.2019.03.003","article-title":"Remote ischemic perconditioning attenuates adverse cardiac remodeling and preserves left ventricular function in a rat model of reperfused myocardial infarction","volume":"285","author":"Pilz","year":"2019","journal-title":"Int. J. Cardiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00395-021-00851-1","article-title":"Vascular conditioning prevents adverse left ventricular remodelling after acute myocardial infarction: A randomised remote conditioning study","volume":"116","author":"Ikonomidis","year":"2021","journal-title":"Basic Res. Cardiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1161\/CIRCRESAHA.116.305348","article-title":"Molecular basis of cardioprotection: Signal transduction in ischemic pre-, post-, and remote conditioning","volume":"116","author":"Heusch","year":"2015","journal-title":"Circ. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.2147\/DDDT.S68715","article-title":"Remote ischemic conditioning improves coronary microcirculation in healthy subjects and patients with heart failure","volume":"8","author":"Fukuda","year":"2014","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1111\/j.1440-1681.2008.05070.x","article-title":"Swimming Training Attenuates Remodeling, Contractile Dysfunction and Congestive Heart Failure in Rats with Moderate and Large Myocardial Infarctions","volume":"36","author":"Portes","year":"2009","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/s41569-018-0007-y","article-title":"Mechanisms of physiological and pathological cardiac hypertrophy","volume":"15","author":"Nakamura","year":"2018","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/S0895-7061(02)02972-2","article-title":"Cardiac angiotensin II: An intracrine hormone?","volume":"15","author":"Schuijt","year":"2002","journal-title":"Am. J. Hypertens."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1456","DOI":"10.1161\/CIRCRESAHA.120.317015","article-title":"Angiotensin-Converting Enzyme 2: SARS-CoV-2 Receptor and Regulator of the Renin-Angiotensin System: Celebrating the 20th Anniversary of the Discovery of ACE2","volume":"126","author":"Gheblawi","year":"2020","journal-title":"Circ. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.jaccao.2020.01.005","article-title":"Repeated Remote Ischemic Conditioning Reduces Doxorubicin-Induced Cardiotoxicity","volume":"2","author":"He","year":"2020","journal-title":"JACC CardioOncol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1111\/wrr.12956","article-title":"Impact of repeated remote ischemic conditioning on diabetic foot ulcers: A proof-of-concept study","volume":"29","author":"Regulski","year":"2021","journal-title":"Wound Repair Regen."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2017\/3920195","article-title":"A Review of the Molecular Mechanisms Underlying the Development and Progression of Cardiac Remodeling","volume":"2017","author":"Schirone","year":"2017","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1161\/CIRCRESAHA.118.314060","article-title":"NHLBI-Sponsored Randomized Trial of Postconditioning During Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction","volume":"124","author":"Traverse","year":"2019","journal-title":"Circ. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"9478","DOI":"10.1111\/jcmm.15607","article-title":"Systematic profiling of ACE2 expression in diverse physiological and pathological conditions for COVID-19\/SARS-CoV-2","volume":"24","author":"Li","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_22","first-page":"4","article-title":"Circulating ACE2 activity correlates with cardiovascular disease development","volume":"17","author":"Fagyas","year":"2016","journal-title":"J. Renin-Angiotensin-Aldosterone Syst."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1002\/ehf2.12794","article-title":"Tenascin-C aggravates ventricular dilatation and angiotensin-converting enzyme activity after myocardial infarction in mice","volume":"7","author":"Santer","year":"2020","journal-title":"ESC Heart Fail."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s11357-020-00300-2","article-title":"Level of the SARS-CoV-2 receptor ACE2 activity is highly elevated in old-aged patients with aortic stenosis: Implications for ACE2 as a biomarker for the severity of COVID-19","volume":"43","author":"Fagyas","year":"2021","journal-title":"Geroscience"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"\u00dari, K., Fagyas, M., M\u00e1nyin\u00e9 Siket, I., Kert\u00e9sz, A., Csan\u00e1di, Z., S\u00e1ndorfi, G., Clemens, M., Fedor, R., Papp, Z., and \u00c9des, I. (2014). New perspectives in the renin-angiotensin-aldosterone system (RAAS) IV: Circulating ACE2 as a biomarker of systolic dysfunction in human hypertension and heart failure. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0087845"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"B\u00e1nhegyi, V., Enyedi, A., F\u00fcl\u00f6p, G., Ol\u00e1h, A., Siket, I., V\u00e1radi, C., Botty\u00e1n, K., L\u00f3di, M., Csongr\u00e1di, A., and Umar, A. (2021). Human Tissue Angiotensin Converting Enzyme (ACE) Activity Is Regulated by Genetic Polymorphisms, Posttranslational Modifications, Endogenous Inhibitors and Secretion in the Serum, Lungs and Heart. Cells, 10.","DOI":"10.3390\/cells10071708"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Fagyas, M., B\u00e1nhegyi, V., \u00dari, K., Enyedi, A., Lizanecz, E., M\u00e1nyin\u00e9 Siket, I., M\u00e1rtha, L., F\u00fcl\u00f6p, G.\u00c1., Radovits, T., and P\u00f3los, M. (2021). Changes in the SARS-CoV-2 cellular receptor ACE2 levels in cardiovascular patients: A potential biomarker for the stratification of COVID-19 patients. GeroScience, accepted by publisher.","DOI":"10.1007\/s11357-021-00467-2"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1016\/j.yjmcc.2006.08.017","article-title":"Troponin phosphorylation and regulatory function in human heart muscle: Dephosphorylation of Ser23\/24 on troponin I could account for the contractile defect in end-stage heart failure","volume":"42","author":"Messer","year":"2007","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1161\/01.RES.86.1.51","article-title":"Myosin Binding Protein C, a Phosphorylation-Dependent Force Regulator in Muscle That Controls the Attachment of Myosin Heads by Its Interaction With Myosin S2","volume":"86","author":"Kunst","year":"2000","journal-title":"Circ. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"15485","DOI":"10.1073\/pnas.1903033116","article-title":"Site-specific phosphorylation of myosin binding protein-C coordinates thin and thick filament activation in cardiac muscle","volume":"116","author":"Ponnam","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.yjmcc.2006.08.016","article-title":"PKC-betaII sensitizes cardiac myofilaments to Ca2+ by phosphorylating troponin I on threonine-144","volume":"41","author":"Wang","year":"2006","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e009540","DOI":"10.1161\/JAHA.118.009540","article-title":"Mitochondrial and Contractile Function of Human Right Atrial Tissue in Response to Remote Ischemic Conditioning","volume":"7","author":"Kleinbongard","year":"2018","journal-title":"J. Am. Heart Assoc."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1152\/physrev.00036.2005","article-title":"Physiology of Local Renin-Angiotensin Systems","volume":"86","author":"Paul","year":"2006","journal-title":"Physiol. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1161\/01.RES.69.2.475","article-title":"Tissue-specific activation of cardiac angiotensin converting enzyme in experimental heart failure","volume":"69","author":"Hirsch","year":"1991","journal-title":"Circ. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1093\/cvr\/cvu163","article-title":"Delayed phospholamban phosphorylation in post-conditioned heart favours Ca2+ normalization and contributes to protection","volume":"103","author":"Inserte","year":"2014","journal-title":"Cardiovasc. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1124\/pr.113.008300","article-title":"Interaction of Risk Factors, Comorbidities, and Comedications with Ischemia\/Reperfusion Injury and Cardioprotection by Preconditioning, Postconditioning, and Remote Conditioning","volume":"66","author":"Ferdinandy","year":"2014","journal-title":"Pharmacol. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1172\/JCI121297","article-title":"Endothelial progerin expression causes cardiovascular pathology through an impaired mechanoresponse","volume":"129","author":"Kiss","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1861","DOI":"10.1097\/HJH.0000000000002097","article-title":"Epigenetic modulation of tenascin C in the heart: Implications on myocardial ischemia, hypertrophy and metabolism","volume":"37","author":"Goncalves","year":"2019","journal-title":"J. Hypertens."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1007\/s12350-017-0994-9","article-title":"Rubidium-82 PET imaging is feasible in a rat myocardial infarction model","volume":"26","author":"Ghotbi","year":"2017","journal-title":"J. Nucl. Cardiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"dmm047704","DOI":"10.1242\/dmm.047704","article-title":"Cardiovascular phenotype of the Dmd(mdx) rat\u2014A suitable animal model for Duchenne muscular dystrophy","volume":"14","author":"Ebner","year":"2021","journal-title":"Dis. Model. Mech."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Fagyas, M., \u00dari, K., Siket, I.M., F\u00fcl\u00f6p, G.\u00c1., Csat\u00f3, V., Darag\u00f3, A., Bocz\u00e1n, J., B\u00e1nyai, E., Szentkir\u00e1lyi, I.E., and Maros, T.M. (2014). New Perspectives in the Renin-Angiotensin-Aldosterone System (RAAS) II: Albumin Suppresses Angiotensin Converting Enzyme (ACE) Activity in Human. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0087844"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/20\/11064\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:14:23Z","timestamp":1760166863000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/20\/11064"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,14]]},"references-count":41,"journal-issue":{"issue":"20","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["ijms222011064"],"URL":"https:\/\/doi.org\/10.3390\/ijms222011064","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,14]]}}}