Protective effect of secretory APE1/Ref‐1 on doxorubicin‐induced cardiotoxicity via suppression of ROS and p53 pathway
Abstract Aims The clinical application of doxorubicin (DOX), a potent anthracycline anticancer drug that effectively treats various malignancies, is limited by its side effects, such as cardiomyopathy. Apurinic/apyrimidinic endonuclease 1/redox factor‐1 (APE1/Ref‐1) is a multifunctional protein that...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2024-04-01
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| Series: | ESC Heart Failure |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/ehf2.14686 |
| _version_ | 1797242794749722624 |
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| author | Soo Yeon An Seon‐Ah Jin Hee Jeong Seo Yu Ran Lee Sungmin Kim Byeong Hwa Jeon Jin‐Ok Jeong |
| author_facet | Soo Yeon An Seon‐Ah Jin Hee Jeong Seo Yu Ran Lee Sungmin Kim Byeong Hwa Jeon Jin‐Ok Jeong |
| author_sort | Soo Yeon An |
| collection | DOAJ |
| description | Abstract Aims The clinical application of doxorubicin (DOX), a potent anthracycline anticancer drug that effectively treats various malignancies, is limited by its side effects, such as cardiomyopathy. Apurinic/apyrimidinic endonuclease 1/redox factor‐1 (APE1/Ref‐1) is a multifunctional protein that can be secreted and is a promising target for the reduction of DOX‐induced inflammation and oxidative stress. We aimed to investigate the protective role of secretory APE1/Ref‐1 against DOX‐induced cardiac injury. Methods and results Designated adenoviral preprotrypsin‐leading sequence APE1/Ref‐1 (Ad‐PPTLS‐APE1/Ref‐1) was used to overexpress secretory APE1/Ref‐1 and assess its role in preventing DOX‐induced cardiomyopathy in vitro. Our findings revealed that exposure to secretory APE1/Ref‐1 significantly decreased N‐terminal pro‐B‐type natriuretic peptide levels in DOX‐treated H9C2 cells. In addition, secretory APE1/Ref‐1 reduced the severity of cardiomyocyte injury and apoptosis in both in vitro and in vivo DOX‐induced cardiotoxicity models. The observed cardioprotective effects of secretory APE1/Ref‐1 were mediated via inhibition of the p53 signalling pathway and enhancement of cell viability through attenuation of oxidative stress in DOX‐treated cardiomyocytes. Conclusions Our study provides evidence that secretory APE1/Ref‐1 has the potential to inhibit DOX‐induced cardiac toxicity by inhibiting oxidative stress and p53 related apoptosis both in vitro and in vivo. These findings suggest that secretory APE1/Ref‐1 supplementation is a promising strategy to attenuate DOX‐induced cardiomyocyte damage in a preclinical model. Further clinical investigations are essential to validate the therapeutic efficacy and safety of the intervention in human subjects. |
| first_indexed | 2024-04-24T18:44:53Z |
| format | Article |
| id | doaj.art-0ff389ac0b26479b859d7c34fbd39d8a |
| institution | Directory Open Access Journal |
| issn | 2055-5822 |
| language | English |
| last_indexed | 2024-04-24T18:44:53Z |
| publishDate | 2024-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | ESC Heart Failure |
| spelling | doaj.art-0ff389ac0b26479b859d7c34fbd39d8a2024-03-27T06:48:04ZengWileyESC Heart Failure2055-58222024-04-011121182119310.1002/ehf2.14686Protective effect of secretory APE1/Ref‐1 on doxorubicin‐induced cardiotoxicity via suppression of ROS and p53 pathwaySoo Yeon An0Seon‐Ah Jin1Hee Jeong Seo2Yu Ran Lee3Sungmin Kim4Byeong Hwa Jeon5Jin‐Ok Jeong6Division of Cardiology, Department of Internal Medicine Chungnam National University Hospital, College of Medicine, Chungnam National University Daejeon Republic of KoreaDivision of Cardiology, Department of Internal Medicine Chungnam National University Hospital, College of Medicine, Chungnam National University Daejeon Republic of KoreaResearch Institute for Medical Sciences, College of Medicine Chungnam National University Daejeon Republic of KoreaResearch Institute for Medical Sciences, College of Medicine Chungnam National University Daejeon Republic of KoreaDepartment of Medical Sciences, College of Medicine Chungnam National University Daejeon Republic of KoreaDepartment of Medical Sciences, College of Medicine Chungnam National University Daejeon Republic of KoreaDivision of Cardiology, Department of Internal Medicine Chungnam National University Hospital, College of Medicine, Chungnam National University Daejeon Republic of KoreaAbstract Aims The clinical application of doxorubicin (DOX), a potent anthracycline anticancer drug that effectively treats various malignancies, is limited by its side effects, such as cardiomyopathy. Apurinic/apyrimidinic endonuclease 1/redox factor‐1 (APE1/Ref‐1) is a multifunctional protein that can be secreted and is a promising target for the reduction of DOX‐induced inflammation and oxidative stress. We aimed to investigate the protective role of secretory APE1/Ref‐1 against DOX‐induced cardiac injury. Methods and results Designated adenoviral preprotrypsin‐leading sequence APE1/Ref‐1 (Ad‐PPTLS‐APE1/Ref‐1) was used to overexpress secretory APE1/Ref‐1 and assess its role in preventing DOX‐induced cardiomyopathy in vitro. Our findings revealed that exposure to secretory APE1/Ref‐1 significantly decreased N‐terminal pro‐B‐type natriuretic peptide levels in DOX‐treated H9C2 cells. In addition, secretory APE1/Ref‐1 reduced the severity of cardiomyocyte injury and apoptosis in both in vitro and in vivo DOX‐induced cardiotoxicity models. The observed cardioprotective effects of secretory APE1/Ref‐1 were mediated via inhibition of the p53 signalling pathway and enhancement of cell viability through attenuation of oxidative stress in DOX‐treated cardiomyocytes. Conclusions Our study provides evidence that secretory APE1/Ref‐1 has the potential to inhibit DOX‐induced cardiac toxicity by inhibiting oxidative stress and p53 related apoptosis both in vitro and in vivo. These findings suggest that secretory APE1/Ref‐1 supplementation is a promising strategy to attenuate DOX‐induced cardiomyocyte damage in a preclinical model. Further clinical investigations are essential to validate the therapeutic efficacy and safety of the intervention in human subjects.https://doi.org/10.1002/ehf2.14686Apurinic apyrimidinic endonuclease 1/redox factor‐1DoxorubicinHeart failurep53 signalling pathwayOxidative stressCardiomyopathy |
| spellingShingle | Soo Yeon An Seon‐Ah Jin Hee Jeong Seo Yu Ran Lee Sungmin Kim Byeong Hwa Jeon Jin‐Ok Jeong Protective effect of secretory APE1/Ref‐1 on doxorubicin‐induced cardiotoxicity via suppression of ROS and p53 pathway ESC Heart Failure Apurinic apyrimidinic endonuclease 1/redox factor‐1 Doxorubicin Heart failure p53 signalling pathway Oxidative stress Cardiomyopathy |
| title | Protective effect of secretory APE1/Ref‐1 on doxorubicin‐induced cardiotoxicity via suppression of ROS and p53 pathway |
| title_full | Protective effect of secretory APE1/Ref‐1 on doxorubicin‐induced cardiotoxicity via suppression of ROS and p53 pathway |
| title_fullStr | Protective effect of secretory APE1/Ref‐1 on doxorubicin‐induced cardiotoxicity via suppression of ROS and p53 pathway |
| title_full_unstemmed | Protective effect of secretory APE1/Ref‐1 on doxorubicin‐induced cardiotoxicity via suppression of ROS and p53 pathway |
| title_short | Protective effect of secretory APE1/Ref‐1 on doxorubicin‐induced cardiotoxicity via suppression of ROS and p53 pathway |
| title_sort | protective effect of secretory ape1 ref 1 on doxorubicin induced cardiotoxicity via suppression of ros and p53 pathway |
| topic | Apurinic apyrimidinic endonuclease 1/redox factor‐1 Doxorubicin Heart failure p53 signalling pathway Oxidative stress Cardiomyopathy |
| url | https://doi.org/10.1002/ehf2.14686 |
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