{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T20:53:26Z","timestamp":1773694406061,"version":"3.50.1"},"reference-count":45,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2018,3,7]],"date-time":"2018-03-07T00:00:00Z","timestamp":1520380800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Doxorubicin (DOXO) administration induces alterations in Connexin 43 (Cx43) expression and localization, thus, inducing alterations in chemical and electrical signal transmission between cardiomyocytes and in intracellular calcium homeostasis even evident after a single administration. This study was designed to evaluate if Diazoxide (DZX), a specific opener of mitochondrial KATP channels widely used for its cardioprotective effects, can fight DOXO-induced cardiotoxicity in a short-time mouse model. DZX (20 mg\/kg i.p.) was administered 30 min before DOXO (10 mg\/kg i.p.) in C57BL\/6j female mice for 1\u20133 or seven days once every other day. A recovery of cardiac parameters, evaluated by Echocardiography, were observed in DZX+DOXO co-treated mice. Western blot analysis performed on heart lysates showed an increase in sarco\/endoplasmic reticulum Ca2+-ATPase (SERCAII) and a reduction in phospholamban (PLB) amounts in DZX+DOXO co-treated mice. A contemporary recovery of intracellular Ca2+-signal, detected spectrofluorometrically by means of FURA-2AM, was observed in these mice. Cx43 expression and localization, analyzed by Western blot and confirmed by immunofluorescence analysis, showed that DZX co-treatement increases Cx43 amount both on sarcoplasmic membrane and on mitochondria. In conclusion, our data demonstrate that, in a short-time mouse model of DOXO-induced cardiotoxicity, DZX exerts its cardioprotective effects also by enhancing the amount Cx43.<\/jats:p>","DOI":"10.3390\/ijms19030757","type":"journal-article","created":{"date-parts":[[2018,3,7]],"date-time":"2018-03-07T12:55:23Z","timestamp":1520427323000},"page":"757","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Diazoxide Improves Mitochondrial Connexin 43 Expression in a Mouse Model of Doxorubicin-Induced Cardiotoxicity"],"prefix":"10.3390","volume":"19","author":[{"given":"Michela","family":"Pecoraro","sequence":"first","affiliation":[{"name":"Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2379-1960","authenticated-orcid":false,"given":"Michele","family":"Ciccarelli","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Salerno, 84084 Baronissi, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antonella","family":"Fiordelisi","sequence":"additional","affiliation":[{"name":"Department of Advanced Biomedical Sciences, Federico II University, 80138 Naples, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8997-835X","authenticated-orcid":false,"given":"Guido","family":"Iaccarino","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, University of Salerno, 84084 Baronissi, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6899-6340","authenticated-orcid":false,"given":"Aldo","family":"Pinto","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9843-8443","authenticated-orcid":false,"given":"Ada","family":"Popolo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,3,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"75","DOI":"10.14712\/18059694.2019.117","article-title":"Anthracycline-induced cardiotoxicity","volume":"43","author":"Hrdina","year":"2000","journal-title":"Acta Med. (Hrad. Kralove)"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1016\/j.yjmcc.2012.03.006","article-title":"Doxorubicin-induced cardiomyopathy: From molecular mechanisms to therapeutic strategies","volume":"52","author":"Octavia","year":"2012","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"56","DOI":"10.4161\/cbt.22628","article-title":"Small molecule kinase inhibitors block the ZAK-dependent inflammatory effects of doxorubicin","volume":"14","author":"Wong","year":"2013","journal-title":"Cancer Biol. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.taap.2013.10.023","article-title":"Keap1 redox-dependent regulation of doxorubicin-induced oxidative stress response in cardiac myoblasts","volume":"274","author":"Nordgren","year":"2014","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.mito.2016.10.008","article-title":"Effects of doxorubicin on cardiac muscle subsarcolemmal and intermyofibrillar mitochondria","volume":"34","author":"Kavazis","year":"2016","journal-title":"Mitochondrion"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1916","DOI":"10.1016\/j.bbamcr.2016.01.021","article-title":"New signal transduction paradigms in anthracycline-induced cardiotoxicity","volume":"1863","author":"Ghigo","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1038\/nm.2919","article-title":"Identification of the molecular basis of doxorubicin-induced cardiotoxicity","volume":"18","author":"Zhang","year":"2012","journal-title":"Nat. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3794","DOI":"10.1200\/JCO.2007.11.9537","article-title":"The heart of the matter","volume":"25","author":"Portera","year":"2007","journal-title":"J. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1021\/tx800002r","article-title":"Cardiotoxicity of antitumor drugs","volume":"21","author":"Menna","year":"2008","journal-title":"Chem. Res. Toxicol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.taap.2016.01.006","article-title":"Inflammatory mediators in a short-time mouse model of doxorubicin-induced cardiotoxicity","volume":"293","author":"Pecoraro","year":"2016","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Pecoraro, M., Rodr\u00edguez-Sinovas, A., Marzocco, S., Ciccarelli, M., Iaccarino, G., Pinto, A., and Popolo, A. (2017). Cardiotoxic Effects of Short-Term Doxorubicin Administration: Involvement of Connexin 43 in Calcium Impairment. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18102121"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.ejphar.2015.10.030","article-title":"Role of connexin 43 in cardiovascular diseases","volume":"768","author":"Pecoraro","year":"2015","journal-title":"Eur. J. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1093\/cvr\/cvp157","article-title":"Connexin43 in cardiomyocyte mitochondria contributes to mitochondrial potassium uptake","volume":"83","author":"Agullo","year":"2009","journal-title":"Cardiovasc. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1111\/j.1582-4934.2011.01516.x","article-title":"Mitochondrial connexin 43 impacts on respiratorycomplex I activity and mitochondrial oxygenconsumption","volume":"16","author":"Boengler","year":"2012","journal-title":"J. Cell. Mol. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/s00395-017-0618-1","article-title":"Mitochondrial Cx43 hemichannels contribute to mitochondrial calcium entry and cell death in the heart","volume":"112","author":"Gadicherla","year":"2017","journal-title":"Basic Res. Cardiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1007\/s12012-014-9305-8","article-title":"Doxorubicin-Mediated Cardiotoxicity: Role of Mitochondrial Connexin 43","volume":"15","author":"Pecoraro","year":"2015","journal-title":"Cardiovasc. Toxicol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0005-2728(03)00109-9","article-title":"Mitochondrial potassium transport: The role of the mitochondrial ATP-sensitive K(+) channel in cardiac function and cardioprotection","volume":"1606","author":"Garlid","year":"2003","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1161\/CIRCRESAHA.112.300514","article-title":"KATP channels and cardiovascular disease: Suddenly a syndrome","volume":"112","author":"Nichols","year":"2013","journal-title":"Circ. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1038\/305147a0","article-title":"ATP-regulated K+ channels in cardiac muscle","volume":"305","author":"Noma","year":"1983","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.jamcollsurg.2015.02.014","article-title":"Diazoxide Cardioprotection Is Independent of Adenosine Triphosphate-Sensitive Potassium Channel Kir6.1 Subunit in Response to Stress","volume":"2","author":"Henn","year":"2015","journal-title":"J. Am. Coll. Surg."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1093\/cvr\/cvm056","article-title":"Regulation of sarcoplasmic reticulum Ca2+ ATPase pump expression and its relevance to cardiac muscle physiology and pathology","volume":"77","author":"Periasamy","year":"2008","journal-title":"Cardiovasc. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.yjmcc.2017.05.002","article-title":"Regulation of cardiac gap junctions by protein phosphatases","volume":"107","author":"Hood","year":"2017","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1007\/s00005-009-0051-8","article-title":"Cardiomyocyte death in doxorubicin-induced cardiotoxicity","volume":"57","author":"Zhang","year":"2009","journal-title":"Arch. Immunol. Ther. Exp. (Warsz)"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1023\/A:1007094214460","article-title":"Adriamycin-induced heart failure: Mechanism and modulation","volume":"207","author":"Singal","year":"2000","journal-title":"Mol. Cell. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1161\/01.CIR.102.5.572","article-title":"Fas-mediated apoptosis in adriamycin-induced cardiomyopathy in rats: In vivo study","volume":"102","author":"Nakamura","year":"2000","journal-title":"Circulation"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1093\/cvr\/cvn133","article-title":"Remodelling of gap junctions and connexin expression in diseased myocardium","volume":"80","author":"Severs","year":"2008","journal-title":"Cardiovasc. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.pharmthera.2013.06.007","article-title":"Multiplicity of effectors of the cardioprotective agent, diazoxide","volume":"140","author":"Coetzee","year":"2013","journal-title":"Pharmacol. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3092","DOI":"10.1016\/j.bpj.2009.01.014","article-title":"Extracellular space attenuates the effect of gap junctional remodeling on wave propagation: A computational study","volume":"96","author":"Cabo","year":"2009","journal-title":"Biophys. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s10863-005-4130-1","article-title":"Mitochondrial ATP-sensitive K+ channels prevent oxidative stress, permeability transition and cell death","volume":"37","author":"Facundo","year":"2005","journal-title":"J. Bioenerg. Biomembr."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1172","DOI":"10.1111\/j.1476-5381.2010.00960.x","article-title":"Pharmacological preconditioning by diazoxide downregulates cardiac l-type Ca(2+)","volume":"161","author":"Gonzales","year":"2010","journal-title":"Br. J. Pharmacol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1038\/nrcardio.2017.23","article-title":"Sarcoplasmic reticulum-mitochondria communication in cardiovascular pathophysiology","volume":"14","author":"Pennanen","year":"2017","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1186\/s12967-014-0323-x","article-title":"Resveratrol ameliorates cardiac dysfunction induced by pressure overload in rats via structural protection and modulation of Ca(2+) cycling proteins","volume":"12","author":"Dong","year":"2014","journal-title":"J. Transl. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1172\/JCI62834","article-title":"Calcium cycling proteins and heart failure: Mechanisms and therapeutics","volume":"123","author":"Marks","year":"2013","journal-title":"J. Clin. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1791","DOI":"10.1007\/s12013-014-0130-2","article-title":"Doxorubicin induces sarcoplasmic reticulum calcium regulation dysfunction via the decrease of SERCA2 and phospholamban expressions in rats","volume":"70","author":"Zhang","year":"2014","journal-title":"Cell Biochem. Biophys."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.cbi.2016.11.012","article-title":"Diazoxide prevents reactive oxygen species and mitochondrial damage, leading to anti-hypertrophic effects","volume":"261","author":"Lucas","year":"2017","journal-title":"Chem. Biol. Interact."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1093\/cvr\/cvs116","article-title":"Calcium-mediated cell death during myocardial reperfusion","volume":"94","author":"Inserte","year":"2012","journal-title":"Cardiovasc. Res."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Hou, S., Shen, P.P., Zhao, M.M., Liu, X.P., Xie, H.Y., Deng, F., and Feng, J.C. (2016). Mechanism of mitochondrial Connexin43\u2019s protection of the neurovascular unit under acute cerebral ischemia-repurfusion injury. Int. J. Mol. Sci., 17.","DOI":"10.3390\/ijms17050679"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"668","DOI":"10.3892\/br.2015.485","article-title":"Ischemic postconditioning improves the expression of cellular membrane connexin 43 and attenuates the reperfusion injury in rat acute myocardial infarction","volume":"3","author":"He","year":"2015","journal-title":"Biomed. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4919","DOI":"10.1073\/pnas.0603154104","article-title":"Change in permeant size selectivity by phosphorylation of connexin 43 gap-junctional hemichannels by PKC","volume":"104","author":"Bao","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1038\/sj.bjp.0706922","article-title":"Diazoxide acts more as a PKC-epsilon activator, and indirectly activates the mitochondrial K(ATP) channel conferring cardioprotection against hypoxic injury","volume":"149","author":"Kim","year":"2006","journal-title":"Br. J. Pharmacol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.exer.2007.10.012","article-title":"Protein Kinase C Epsilon Activates Lens Mitochondrial Cytochrome C Oxidase Subunit IV During Hypoxia","volume":"86","author":"Barnett","year":"2008","journal-title":"Exp. Eye Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.tox.2013.08.001","article-title":"PKC\u025b mediates serine phosphorylation of connexin43 induced by lysophosphatidylcholine in neonatal rat cardiomyocytes","volume":"314","author":"Liao","year":"2013","journal-title":"Toxicology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1006\/abbi.2000.2131","article-title":"Regulation of gap junctions by phosphorylation of connexins","volume":"384","author":"Lampe","year":"2000","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"697305","DOI":"10.1155\/2013\/697305","article-title":"Anticonvulsant effect of Diazoxide against Dichlorvos-induced seizures in mice","volume":"2013","author":"Jazayeri","year":"2013","journal-title":"Sci. World J."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.cardiores.2005.04.014","article-title":"Connexin 43 in cardiomyocyte mitochondria and its increase by ischemic preconditioning","volume":"67","author":"Boengler","year":"2005","journal-title":"Cardiovasc. Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/3\/757\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T14:57:51Z","timestamp":1760194671000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/3\/757"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,7]]},"references-count":45,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2018,3]]}},"alternative-id":["ijms19030757"],"URL":"https:\/\/doi.org\/10.3390\/ijms19030757","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,3,7]]}}}