{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T15:12:41Z","timestamp":1784128361578,"version":"3.55.0"},"reference-count":47,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T00:00:00Z","timestamp":1760486400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006109","name":"VEGA","doi-asserted-by":"crossref","award":["2\/0006\/23"],"award-info":[{"award-number":["2\/0006\/23"]}],"id":[{"id":"10.13039\/501100006109","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100005357","name":"Slovak Research and Development Agency","doi-asserted-by":"crossref","award":["APVV-21-0410"],"award-info":[{"award-number":["APVV-21-0410"]}],"id":[{"id":"10.13039\/501100005357","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100005357","name":"Slovak Research and Development Agency","doi-asserted-by":"crossref","award":["VV-MVP-24-0278"],"award-info":[{"award-number":["VV-MVP-24-0278"]}],"id":[{"id":"10.13039\/501100005357","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["ITMS2014+: 313011AVG3"],"award-info":[{"award-number":["ITMS2014+: 313011AVG3"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry of Health of the Czech Republic within the project for the development of research organization","award":["00023001"],"award-info":[{"award-number":["00023001"]}]},{"name":"National Institute for Research of Metabolic and Cardiovascular Diseases","award":["LX22NPO5104"],"award-info":[{"award-number":["LX22NPO5104"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Pressure overload in non-treated or resistant hypertension (HTN) increases the risk of heart failure (HF) as well as the occurrence of fatal ventricular arrhythmias and stroke-provoking atrial fibrillation (AF), while perturbed connexin-43 (Cx43) and Cx40 might be involved. In addition, kidney dysfunction may facilitate hemodynamic volume overload and congestive HF. We investigated the impact of volume overload on Cx43 and Cx40 in right and left heart atria of hypertensive pressure overloaded Ren-2 transgenic (TGR) strain and normotensive Hannover Sprague Dawley (HSD) rats, as well as the efficacy of renin\u2013angiotensin blockade with trandolapril and losartan. Key novel findings revealed lower levels of Cx43 and Cx40 proteins in left as well as right heart atria in pressure overloaded hypertensive rats compared to normotensive rats. There was a significant decrease in Cx43 and Cx40 proteins due to volume overload in both atria of normotensive as well as hypertensive rats. Treatment with trandolapril increased Cx43 and Cx40 levels in right and left heart atria of normotensive as well as hypertensive volume overloaded rats. While losartan increased Cx43 and did not affect Cx40 in left and right heart atria of volume overloaded rats. Findings of this study point out that right heart atria of normotensive as well as hypertensive rats are more susceptible to volume overload comparing to the left heart atria. Trandolapril attenuated pro-arrhythmic downregulation of Cx43 and Cx40 in atria of volume overloaded normotensive as well as hypertensive rats. This fact as well as examining AF inducibility requires further investigation.<\/jats:p>","DOI":"10.3390\/biom15101457","type":"journal-article","created":{"date-parts":[[2025,10,15]],"date-time":"2025-10-15T11:57:42Z","timestamp":1760529462000},"page":"1457","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Trandolapril Attenuates Pro-Arrhythmic Downregulation of Cx43 and Cx40 in Atria of Volume Overloaded Hypertensive and Normotensive Rats"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0438-3956","authenticated-orcid":false,"given":"Mat\u00fa\u0161","family":"S\u00fdkora","sequence":"first","affiliation":[{"name":"Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 841 04 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1499-7687","authenticated-orcid":false,"given":"Katar\u00edna","family":"Ondrej\u00e1k Andelov\u00e1","sequence":"additional","affiliation":[{"name":"Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 841 04 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Mrvov\u00e1","sequence":"additional","affiliation":[{"name":"Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 841 04 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Szeiffov\u00e1 Ba\u010dov\u00e1","sequence":"additional","affiliation":[{"name":"Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 841 04 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5904-4249","authenticated-orcid":false,"given":"Narcis","family":"Tribulov\u00e1","sequence":"additional","affiliation":[{"name":"Centre of Experimental Medicine, Institute for Heart Research, Slovak Academy of Sciences, 841 04 Bratislava, Slovakia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,15]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1161\/HYPERTENSIONAHA.122.20141","article-title":"Systolic Blood Pressure Time in Target Range and Major Adverse Kidney and Cardiovascular Events","volume":"80","author":"Buckley","year":"2023","journal-title":"Hypertension"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3757","DOI":"10.1007\/s00210-023-02561-y","article-title":"The treatment with sGC stimulator improves survival of hypertensive rats in response to volume-overload induced by aorto-caval fistula","volume":"396","author":"Gawrys","year":"2023","journal-title":"Naunyn. Schmiedebergs. Arch. Pharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Sykora, M., Andelova, K., Szeiffova Bacova, B., Egan Benova, T., Martiskova, A., Knezl, V., and Tribulova, N. (2023). Hypertension Induces Pro-arrhythmic Cardiac Connexome Disorders: Protective Effects of Treatment. Biomolecules, 13.","DOI":"10.3390\/biom13020330"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1093\/eurheartj\/ehaa1061","article-title":"The year in cardiovascular medicine 2020: Heart failure and cardiomyopathies","volume":"42","author":"Bueno","year":"2021","journal-title":"Eur. Heart J."},{"key":"ref_5","first-page":"CJ-25-0002","article-title":"JCS\/JHFS 2025 Guideline on Diagnosis and Treatment of Heart Failure","volume":"89","author":"Kitai","year":"2025","journal-title":"Circ. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1016\/0895-7061(95)00400-9","article-title":"The hypertensive Ren-2 transgenic rat TGR(mREN2)27 in hypertension research: Characteristics and functional aspects","volume":"9","author":"Langheinrich","year":"1996","journal-title":"Am. J. Hypertens."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Sykora, M., Kratky, V., Cervenka, L., Kopkan, L., Tribulova, N., and Szeiffova Bacova, B. (2023). The treatment with trandolapril and losartan attenuates pressure and volume overload alternations of cardiac connexin-43 and extracellular matrix in Ren-2 transgenic rats. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-48259-2"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Jarkovsk\u00e1, D., Miklovi\u010d, M., \u0160v\u00edglerov\u00e1, J., \u010cervenka, L., \u0160karoupkov\u00e1, P., Melenovsk\u00fd, V., and \u0160tengl, M. (2021). Effects of Trandolapril on Structural, Contractile and Electrophysiological Remodeling in Experimental Volume Overload Heart Failure. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.729568"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1152\/ajpheart.01137.2009","article-title":"Reduction of fibrosis-related arrhythmias by chronic renin-angiotensin- aldosterone system inhibitors in an aged mouse model","volume":"299","author":"Stein","year":"2010","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1093\/ehjcvp\/pvaf012","article-title":"New pharmacological agents and novel cardiovascular pharmacotherapy strategies in 2024","volume":"11","author":"Tamargo","year":"2025","journal-title":"Eur. Heart J. Cardiovasc. Pharmacother."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Kratky, V., Vanourkova, Z., Sykora, M., Bacova, B.S., Hruskova, Z., Kikerlova, S., Huskova, Z., and Kopkan, L. (2021). AT1 receptor blocker, but not an ACE inhibitor, prevents kidneys from hypoperfusion during congestive heart failure in normotensive and hypertensive rats. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-83906-6"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1093\/cvr\/cvae268","article-title":"A novel approach to modelling acute cardiac decompensation in rats","volume":"121","author":"Thiele","year":"2025","journal-title":"Cardiovasc. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1093\/cvr\/cvae265","article-title":"Stretch regulation of \u03b22-Adrenoceptor signalling in cardiomyocytes requires caveolae","volume":"121","author":"Fu","year":"2025","journal-title":"Cardiovasc. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1161\/CIRCRESAHA.117.311402","article-title":"Hypertension and atrial fibrillation: Doubts and certainties from basic and clinical studies","volume":"122","author":"Verdecchia","year":"2018","journal-title":"Circ. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1248\/bpb.b22-00031","article-title":"Chronic Volume Overload Caused by Abdominal Aorto-Venocaval Shunt Provides Arrhythmogenic Substrates in the Rat Atrium","volume":"45","author":"Aimoto","year":"2022","journal-title":"Biol. Pharm. Bull."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.jphs.2017.12.009","article-title":"Influence of chronic volume overload-induced atrial remodeling on electrophysiological responses to cholinergic receptor stimulation in the isolated rat atria","volume":"136","author":"Cao","year":"2018","journal-title":"J. Pharmacol. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.jphs.2019.11.003","article-title":"Acehytisine suppresses atrial fibrillation in rats with dilated atria caused by chronic volume overload","volume":"142","author":"Cao","year":"2020","journal-title":"J. Pharmacol. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/S0735-1097(03)00578-3","article-title":"Fibrosis of the left atria during progression of heart failure is associated with increased matrix metalloproteinases in the rat","volume":"42","author":"Boixel","year":"2003","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1093\/cvr\/cvab035","article-title":"The effects of cardiac stretch on atrial fibroblasts: Analysis of the evidence and potential role in atrial fibrillation","volume":"118","author":"Li","year":"2022","journal-title":"Cardiovasc. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1152\/physrev.00025.2003","article-title":"Basic Mechanisms of Cardiac Impulse Propagation and Associated Arrhythmias","volume":"84","author":"Rudy","year":"2004","journal-title":"Physiol. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.hrthm.2009.12.009","article-title":"Role of inflammation and oxidative stress in atrial fibrillation","volume":"7","author":"Li","year":"2010","journal-title":"Heart Rhythm"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Dhein, S., and Salameh, A. (2021). Remodeling of cardiac gap junctional cell\u2013cell coupling. Cells, 10.","DOI":"10.3390\/cells10092422"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/s41569-024-01103-0","article-title":"Extracellular matrix in vascular homeostasis and disease","volume":"22","author":"Zhang","year":"2025","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1093\/ehjcvp\/pvaf015","article-title":"Emerging antihypertensive therapies and cardiovascular, kidney, and metabolic outcomes: A Mendelian randomization study","volume":"11","author":"Le","year":"2025","journal-title":"Eur. Heart J. Cardiovasc. Pharmacother."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1016\/0003-2697(84)90084-8","article-title":"A method to reduce interference by sucrose in the detection of thiobarbituric acid-reactive substances","volume":"137","author":"Shlafer","year":"1984","journal-title":"Anal. Biochem."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Lojda, Z., Gossrau, R., and Schiebler, T.H. (1976). Enzymhistochemische Methoden, Springer.","DOI":"10.1007\/978-3-662-11693-7"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"229","DOI":"10.2170\/jjphysiol.48.229","article-title":"Adaptive changes in the capillary network in the left ventricle of rat heart","volume":"48","author":"Koyama","year":"1998","journal-title":"Jpn. J. Physiol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Andelova, K., Szeiffova Bacova, B., Sykora, M., Pavelka, S., Rauchova, H., and Tribulova, N. (2022). Cardiac Cx43 Signaling Is Enhanced and TGF-\u03b21\/SMAD2\/3 Suppressed in Response to Cold Acclimation and Modulated by Thyroid Status in Hairless SHRM. Biomedicines, 10.","DOI":"10.3390\/biomedicines10071707"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Sykora, M., Kratky, V., Kopkan, L., Tribulova, N., and Szeiffova Bacova, B. (2023). Anti-Fibrotic Potential of Angiotensin (1-7) in Hemodynamically Overloaded Rat Heart. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24043490"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1177\/1747493019897870","article-title":"Global epidemiology of atrial fibrillation: An increasing epidemic and public health challenge","volume":"16","author":"Lippi","year":"2021","journal-title":"Int. J. Stroke"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/ncpcardio1414","article-title":"Pathophysiology of concomitant atrial fibrillation and heart failure: Implications for management","volume":"6","author":"Gersh","year":"2009","journal-title":"Nat. Clin. Pract. Cardiovasc. Med."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Havlenova, T., Skaroupkova, P., Miklovic, M., Behounek, M., Chmel, M., Jarkovska, D., Sviglerova, J., Stengl, M., Kolar, M., and Novotny, J. (2021). Right versus left ventricular remodeling in heart failure due to chronic volume overload. Sci. Rep., 11.","DOI":"10.1038\/s41598-021-96618-8"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1161\/CIRCULATIONAHA.114.012975","article-title":"Molecular Mechanisms of RV failure","volume":"132","author":"Reddy","year":"2016","journal-title":"Circulation"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"E20","DOI":"10.1093\/cvr\/cvab228","article-title":"Management of cardiac fibrosis is the largest unmet medical need in heart failure","volume":"118","year":"2022","journal-title":"Cardiovasc. Res."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Gon\u00e7alves, P.R., Nascimento, L.D., Gerlach, R.F., Rodrigues, K.E., and Prado, A.F. (2022). Matrix Metalloproteinase 2 as a Pharmacological Target in Heart Failure. Pharmaceuticals, 15.","DOI":"10.3390\/ph15080920"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1093\/cvr\/cvaf017","article-title":"Immune cells and arrhythmias","volume":"121","author":"Keefe","year":"2025","journal-title":"Cardiovasc. Res."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Andelova, K., Sykora, M., Farkasova, V., Stankovicova, T., Szeiffova Bacova, B., Knezl, V., Egan Benova, T., Pravenec, M., and Tribulova, N. (2024). Acclimation of Hairless Spontaneously Hypertensive Rat to Ambient Temperature Attenuates Hypertension-Induced Pro-Arrhythmic Downregulation of Cx43 in the Left Heart Ventricle of Males. Biomolecules, 14.","DOI":"10.3390\/biom14121509"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1090","DOI":"10.1007\/s12012-024-09884-z","article-title":"Potential Role of Dipeptidyl Peptidase\u22124 in Regulating Mitochondria and Oxidative Stress in Cardiomyocytes","volume":"24","author":"Lee","year":"2024","journal-title":"Cardiovasc. Toxicol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1006\/jmcc.2001.1389","article-title":"Expression and activity of ectopeptidases in fibrillating human atria","volume":"33","author":"Lendeckel","year":"2001","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"La Vecchia, G., Fumarulo, I., Caff\u00e8, A., Chiatto, M., Montone, R.A., and Aspromonte, N. (2024). Microvascular Dysfunction across the Spectrum of Heart Failure Pathology: Pathophysiology, Clinical Features and Therapeutic Implications. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25147628"},{"key":"ref_41","first-page":"625","article-title":"New aspects of pathogenesis of atrial fibrillation: Remodeling of intercalated discs","volume":"66","author":"Tribulova","year":"2015","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1161\/01.CIR.0000090688.49283.67","article-title":"Electrical remodeling of the atria in congestive heart failure: Electrophysiological and electroanatomic mapping in humans","volume":"108","author":"Sanders","year":"2003","journal-title":"Circulation"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/S0248-4900(02)00014-X","article-title":"Connexins, gap junctional intercellular communication and kinases","volume":"94","author":"Cruciani","year":"2002","journal-title":"Biol. Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.cytogfr.2024.10.002","article-title":"Central role of Galectin-3 at the cross-roads of cardiac inflammation and fibrosis: Implications for heart failure and transplantation","volume":"80","author":"Seropian","year":"2024","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.1161\/CIRCULATIONAHA.121.055732","article-title":"Extracellular Matrix in Heart Failure: Role of ADAMTS5 in Proteoglycan Remodeling","volume":"144","author":"Radovits","year":"2021","journal-title":"Circulation"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"813","DOI":"10.33549\/physiolres.934488","article-title":"Apelin-13 Regulates Angiotensin II-Induced Cx43 Downregulation and Autophagy via the AMPK\/mTOR Signaling Pathway in HL-1 Cells","volume":"69","author":"Chen","year":"2020","journal-title":"Physiol. Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1631\/jzus.2006.B0648","article-title":"Effects of angiotensin II on connexin 43 of VSMCs in arteriosclerosis","volume":"7","author":"Cai","year":"2006","journal-title":"J. Zhejiang Univ. Sci. B"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/10\/1457\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T04:29:30Z","timestamp":1760675370000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/15\/10\/1457"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,15]]},"references-count":47,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2025,10]]}},"alternative-id":["biom15101457"],"URL":"https:\/\/doi.org\/10.3390\/biom15101457","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,15]]}}}