{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:05:09Z","timestamp":1785416709315,"version":"3.56.0"},"reference-count":42,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["1344\/15"],"award-info":[{"award-number":["1344\/15"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]},{"award":["1344\/15"],"award-info":[{"award-number":["1344\/15"]}],"id":[{"id":"https:\/\/ror.org\/04sazxf24","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Obstructive sleep apnea (OSA) syndrome is characterized by repetitive nocturnal airway obstruction and is associated with intermittent hypoxia (IH). The leading cause of death among OSA patients is cardiovascular morbidity, which is greatly enhanced by IH. Despite the existence of standard treatment, cardiovascular morbidity remains unaddressed. Given the central role of IH in OSA-related cardiac damage, the present study aimed to elucidate the mechanisms underlying IH-induced cardiac injury in order to better understand and potentially improve upon current therapeutic approaches. Using human embryonic stem cell-derived cardiomyocytes (hESC-CMs) as a novel in vitro model, IH was successfully induced, and its effects on key signaling pathways were investigated. Following IH exposure, significant activation of ERK1\/2, ERK5, and Erbin was demonstrated. Notably, the concurrent increase in both ERK1\/2 activation and Erbin expression following IH suggests a more complex regulatory relationship between these molecules than previously appreciated. Furthermore, pathway-specific inhibition of ERK1\/2 and ERK5 attenuated the IH-induced decline in beating rate, with significant restoration, following normoxic recovery. This study provides an innovative approach for in vitro investigation of OSA-associated cardiovascular morbidity and supports the search for novel pharmacological agents and molecular targets to improve the diagnosis and treatment of affected patients.<\/jats:p>","DOI":"10.3390\/ijms27156804","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T13:53:31Z","timestamp":1785333211000},"page":"6804","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In Vitro Modelling of Obstructive Sleep Apnea by Intermittent Hypoxia of Human Embryonic Stem Cell-Derived Cardiomyocytes: Expression of ERK1\/2, ERK5 and Erbin"],"prefix":"10.3390","volume":"27","author":[{"given":"Danielle","family":"Regev","sequence":"first","affiliation":[{"name":"Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharon","family":"Etzion","sequence":"additional","affiliation":[{"name":"Regenerative Medicine & Stem Cell Research Center, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aviv","family":"Goldbart","sequence":"additional","affiliation":[{"name":"Soroka University Medical Center, Department of Pediatrics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"},{"name":"Pediatric Pulmonary and Sleep Research Laboratory, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9289-8898","authenticated-orcid":false,"given":"Jacob","family":"Gopas","sequence":"additional","affiliation":[{"name":"Shraga Segal Department of Microbiology, Immunology and Genetics, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"210269","DOI":"10.1183\/16000617.0269-2021","article-title":"Cardiac consequences of intermittent hypoxia: A matter of dose? A systematic review and meta-analysis in rodents","volume":"31","author":"Belaidi","year":"2022","journal-title":"Eur. Respir. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.4065\/79.8.1036","article-title":"Obstructive sleep apnea and cardiovascular disease","volume":"79","author":"Parish","year":"2004","journal-title":"Mayo Clin. Proc."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"101871","DOI":"10.1016\/j.smrv.2023.101871","article-title":"Prevalence of obstructive sleep apnea (OSA) among preschool aged children in the general population: A systematic review","volume":"73","author":"Magnusdottir","year":"2024","journal-title":"Sleep Med. Rev."},{"key":"ref_4","first-page":"e4858","article-title":"The Association of Obstructive Sleep Apnea and Hypertension","volume":"11","author":"Patel","year":"2019","journal-title":"Cureus"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1016\/S2213-2600(19)30198-5","article-title":"Estimation of the global prevalence and burden of obstructive sleep apnoea: A literature-based analysis","volume":"7","author":"Benjafield","year":"2019","journal-title":"Lancet Respir. Med."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Cebola, P., Caro\u00e7a, C., Donato, H., Dias, S., Pa\u00e7o, J., and Manso, C. (2025). Computed tomography versus sleep endoscopy (DISE) to predict the effectiveness of mandibular advancement device in adult patients with obstructive sleep apnea: A systematic review. PLoS ONE, 20.","DOI":"10.1371\/journal.pone.0327974"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1378\/chest.14-0500","article-title":"Intermittent hypoxemia and OSA: Implications for comorbidities","volume":"147","author":"Dewan","year":"2015","journal-title":"Chest"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1183\/09031936.00027406","article-title":"Sleep apnoea as an independent risk factor for cardiovascular disease: Current evidence, basic mechanisms and research priorities","volume":"29","author":"McNicholas","year":"2007","journal-title":"Eur. Respir. J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"zsab264","DOI":"10.1093\/sleep\/zsab264","article-title":"Continuous positive airway pressure and adverse cardiovascular events in obstructive sleep apnea: Are participants of randomized trials representative of sleep clinic patients?","volume":"45","author":"Reynor","year":"2022","journal-title":"Sleep"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1056\/NEJMoa1606599","article-title":"CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea","volume":"375","author":"McEvoy","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.5665\/sleep.3236","article-title":"A pro-inflammatory role for nuclear factor kappa B in childhood obstructive sleep apnea syndrome","volume":"36","author":"Israel","year":"2013","journal-title":"Sleep"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"22115","DOI":"10.1038\/s41598-020-79187-0","article-title":"Nuclear factor kappa B activation in cardiomyocytes by serum of children with obstructive sleep apnea syndrome","volume":"10","author":"Goldbart","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Haddad, H., Etzion, S., Rabinski, T., Ofir, R., Regev, D., Etzion, Y., Gopas, J., and Goldbart, A. (2021). The Effect of Sera from Children with Obstructive Sleep Apnea Syndrome (OSAS) on Human Cardiomyocytes Differentiated from Human Embryonic Stem Cells. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111418"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Regev, D., Etzion, S., Haddad, H., Gopas, J., and Goldbart, A. (2022). Obstructive Sleep Apnea Syndrome In Vitro Model: Controlled Intermittent Hypoxia Stimulation of Human Stem Cells-Derived Cardiomyocytes. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231810272"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2351","DOI":"10.1016\/j.biocel.2009.08.002","article-title":"Cardiac hypertrophy: Targeting Raf\/MEK\/ERK1\/2-signaling","volume":"41","author":"Lorenz","year":"2009","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"7440","DOI":"10.1073\/pnas.1221999110","article-title":"Interference with ERK Thr188 phosphorylation impairs pathological but not physiological cardiac hypertrophy","volume":"110","author":"Ruppert","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.pharmthera.2010.04.005","article-title":"Molecular distinction between physiological and pathological cardiac hypertrophy: Experimental findings and therapeutic strategies","volume":"128","author":"Bernardo","year":"2010","journal-title":"Pharmacol. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e1188241","DOI":"10.1080\/19420889.2016.1188241","article-title":"The function of Shoc2: A scaffold and beyond","volume":"9","author":"Jang","year":"2016","journal-title":"Commun. Integr. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5902","DOI":"10.1073\/pnas.1320350111","article-title":"Erbin is a negative modulator of cardiac hypertrophy","volume":"111","author":"Rachmin","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Paudel, R., Fusi, L., and Schmidt, M. (2021). The MEK5\/ERK5 Pathway in Health and Disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22147594"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Pena, E., Brito, J., El Alam, S., and Siques, P. (2020). Oxidative stress, kinase activity and inflammatory implications in right ventricular hypertrophy and heart failure under hypobaric hypoxia. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176421"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1016\/j.cellsig.2011.01.006","article-title":"HB-EGF induces cardiomyocyte hypertrophy via an ERK5-MEF2A-COX2 signaling pathway","volume":"23","author":"Lee","year":"2011","journal-title":"Cell. Signal."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.1016\/j.cellsig.2012.07.007","article-title":"ERK5: Structure, regulation and function","volume":"24","author":"Wilm","year":"2012","journal-title":"Cell. Signal."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3120","DOI":"10.1016\/j.apsb.2021.03.010","article-title":"PD0325901, an ERK inhibitor, enhances the efficacy of PD-1 inhibitor in non-small cell lung carcinoma","volume":"11","author":"Luo","year":"2021","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1016\/j.jacc.2016.11.069","article-title":"Sleep Apnea: Types, Mechanisms, and Clinical Cardiovascular Consequences","volume":"69","author":"Javaheri","year":"2017","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_26","first-page":"142","article-title":"A comprehensive review of obstructive sleep apnea","volume":"14","author":"Abbasi","year":"2021","journal-title":"Sleep Sci."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Gallo, S., Vitacolonna, A., Bonzano, A., Comoglio, P., and Crepaldi, T. (2019). ERK: A key player in the pathophysiology of cardiac hypertrophy. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20092164"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Gilbert, C.J., Longenecker, J.Z., and Accornero, F. (2021). ERK1\/2: An Integrator of Signals That Alters Cardiac Homeostasis and Growth. Biology, 10.","DOI":"10.3390\/biology10040346"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Kong, T., Liu, M., Ji, B., Bai, B., Cheng, B., and Wang, C. (2019). Role of the Extracellular Signal-Regulated Kinase 1\/2 Signaling Pathway in Ischemia-Reperfusion Injury. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.01038"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e65512","DOI":"10.7554\/eLife.65512","article-title":"Human Erbb2-induced Erk activity robustly stimulates cycling and functional remodeling of rat and human cardiomyocytes","volume":"10","author":"Strash","year":"2021","journal-title":"eLife"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1007\/s00204-015-1477-x","article-title":"Pathophysiology of cardiac hypertrophy and heart failure: Signaling pathways and novel therapeutic targets","volume":"89","author":"Tham","year":"2015","journal-title":"Arch. Toxicol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"eadu5769","DOI":"10.1126\/scisignal.adu5769","article-title":"mTORC1 and nuclear ERK spatially control translation in cardiomyocytes through 4EBP1 phosphorylation","volume":"19","author":"Uchida","year":"2026","journal-title":"Sci. Signal."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1570","DOI":"10.1016\/j.ijcard.2012.04.093","article-title":"\u03b22-AR-induced Her2 transactivation mediated by Erbin confers protection from apoptosis in cardiomyocytes","volume":"167","author":"Shi","year":"2013","journal-title":"Int. J. Cardiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/j.pcad.2008.03.002","article-title":"Cardiovascular Complications of Obstructive Sleep Apnea Syndrome: Evidence from Children","volume":"51","author":"Bhattacharjee","year":"2009","journal-title":"Prog. Cardiovasc. Dis."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1007\/s00424-014-1462-x","article-title":"Heart failure-specific changes in protein kinase signalling","volume":"466","author":"Lorenz","year":"2014","journal-title":"Pfl\u00fcgers Arch. Eur. J. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Kontaridis, M.I., Geladari, E.V., and Geladari, C.V. (2015). Pathways to myocardial hypertrophy. Introduction to Translational Cardiovascular Research, Springer International Publishing.","DOI":"10.1007\/978-3-319-08798-6_10"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1038\/s41580-020-0255-7","article-title":"ERK signalling: A master regulator of cell behaviour, life and fate","volume":"21","author":"Lavoie","year":"2020","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1161\/CIRCULATIONAHA.118.037227","article-title":"Inducible Pluripotent Stem Cell-Derived Cardiomyocytes Reveal Aberrant Extracellular Regulated Kinase 5 and Mitogen-Activated Protein Kinase Kinase 1\/2 Signaling Concomitantly Promote Hypertrophic Cardiomyopathy in RAF1-Associated Noonan Syndrome","volume":"140","author":"Miller","year":"2019","journal-title":"Circulation"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1001\/jama.2020.3514","article-title":"Diagnosis and Management of Obstructive Sleep Apnea: A review","volume":"323","author":"Gottlieb","year":"2020","journal-title":"JAMA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.jacc.2010.08.627","article-title":"Obstructive sleep apnea and heart failure: Pathophysiologic and therapeutic implications","volume":"57","author":"Kasai","year":"2011","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1038\/nrcardio.2012.141","article-title":"Mechanisms of cardiac dysfunction in obstructive sleep apnea","volume":"9","author":"Baguet","year":"2012","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Choi, S.-C., Seo, H.-R., Cui, L.-H., Song, M.-H., Noh, J.-M., Kim, K.-S., Choi, J.-H., Kim, J.-H., Park, C.-Y., and Joo, H.J. (2021). Modeling Hypoxic Stress In Vitro Using Human Embryonic Stem Cells Derived Cardiomyocytes Matured by FGF4 and Ascorbic Acid Treatment. Cells, 10.","DOI":"10.3390\/cells10102741"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6804\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T13:54:20Z","timestamp":1785333260000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6804"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,29]]},"references-count":42,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27156804"],"URL":"https:\/\/doi.org\/10.3390\/ijms27156804","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,29]]}}}