Interleukin-10 Mitigates Doxorubicin-Induced Endoplasmic Reticulum Stress as Well as Cardiomyopathy
The use of doxorubicin (Dox) in cancer patients carries the risk of cardiotoxicity via an increase in oxidative stress, mitochondrial dysfunction, and disturbed endoplasmic reticulum (ER) homeostasis in cardiomyocytes. The present study explores which of the ER transmembrane sensors is involved in D...
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MDPI AG
2022-04-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/10/4/890 |
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| author | Akshi Malik Ashim K. Bagchi Davinder S. Jassal Pawan K. Singal |
| author_facet | Akshi Malik Ashim K. Bagchi Davinder S. Jassal Pawan K. Singal |
| author_sort | Akshi Malik |
| collection | DOAJ |
| description | The use of doxorubicin (Dox) in cancer patients carries the risk of cardiotoxicity via an increase in oxidative stress, mitochondrial dysfunction, and disturbed endoplasmic reticulum (ER) homeostasis in cardiomyocytes. The present study explores which of the ER transmembrane sensors is involved in Dox-induced apoptosis and whether interleukin-10 (IL-10) has any mitigating effect. There was a time-related increase in apoptosis in cardiomyocytes exposed to 5.43 µg/mL Dox for 0 to 48 h. Dox treatment for 24 h significantly upregulated glucose-regulated proteins 78 and 94, protein disulfide isomerase, cleavage of activating transcription factor 6α, and X-box binding protein 1. These Dox-induced changes in ER stress proteins as well as apoptosis were blunted by IL-10 (10 ng/mL). In Dox-exposed cardiomyocytes, IL-10 also promoted expression of protein kinase-like endoplasmic reticulum kinase and inositol-requiring kinase 1α, which helped in maintaining ER homeostasis. Additionally, under Dox-treatment, IL-10 downregulated caspase-12 activation as well as phosphorylation of c-JUN NH2-terminal kinase, thereby promoting cardiomyocyte survival. IL-10 was able to reduce the overexpression of mitochondrial apoptotic proteins caspase-3 as well as Bax, which were upregulated upon Dox treatment. Thus, a reduction in Dox-induced ER stress as well as apoptosis through IL-10 may provide a significant benefit in improving cardiac function. |
| first_indexed | 2024-03-09T11:06:44Z |
| format | Article |
| id | doaj.art-0ff435f058f5467cb1e9fd3e2f7879d2 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-09T11:06:44Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-0ff435f058f5467cb1e9fd3e2f7879d22023-12-01T00:54:56ZengMDPI AGBiomedicines2227-90592022-04-0110489010.3390/biomedicines10040890Interleukin-10 Mitigates Doxorubicin-Induced Endoplasmic Reticulum Stress as Well as CardiomyopathyAkshi Malik0Ashim K. Bagchi1Davinder S. Jassal2Pawan K. Singal3Department of Physiology and Pathophysiology, Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, MB R2H 2A6, CanadaDepartment of Internal Medicine, Cardiology Division, Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USADepartment of Physiology and Pathophysiology, Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, MB R2H 2A6, CanadaDepartment of Physiology and Pathophysiology, Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, University of Manitoba, Winnipeg, MB R2H 2A6, CanadaThe use of doxorubicin (Dox) in cancer patients carries the risk of cardiotoxicity via an increase in oxidative stress, mitochondrial dysfunction, and disturbed endoplasmic reticulum (ER) homeostasis in cardiomyocytes. The present study explores which of the ER transmembrane sensors is involved in Dox-induced apoptosis and whether interleukin-10 (IL-10) has any mitigating effect. There was a time-related increase in apoptosis in cardiomyocytes exposed to 5.43 µg/mL Dox for 0 to 48 h. Dox treatment for 24 h significantly upregulated glucose-regulated proteins 78 and 94, protein disulfide isomerase, cleavage of activating transcription factor 6α, and X-box binding protein 1. These Dox-induced changes in ER stress proteins as well as apoptosis were blunted by IL-10 (10 ng/mL). In Dox-exposed cardiomyocytes, IL-10 also promoted expression of protein kinase-like endoplasmic reticulum kinase and inositol-requiring kinase 1α, which helped in maintaining ER homeostasis. Additionally, under Dox-treatment, IL-10 downregulated caspase-12 activation as well as phosphorylation of c-JUN NH2-terminal kinase, thereby promoting cardiomyocyte survival. IL-10 was able to reduce the overexpression of mitochondrial apoptotic proteins caspase-3 as well as Bax, which were upregulated upon Dox treatment. Thus, a reduction in Dox-induced ER stress as well as apoptosis through IL-10 may provide a significant benefit in improving cardiac function.https://www.mdpi.com/2227-9059/10/4/890doxorubicin-induced cardiomyopathyinterleukin-10activating transcription factor 6αendoplasmic reticulum stress-induced apoptosis |
| spellingShingle | Akshi Malik Ashim K. Bagchi Davinder S. Jassal Pawan K. Singal Interleukin-10 Mitigates Doxorubicin-Induced Endoplasmic Reticulum Stress as Well as Cardiomyopathy Biomedicines doxorubicin-induced cardiomyopathy interleukin-10 activating transcription factor 6α endoplasmic reticulum stress-induced apoptosis |
| title | Interleukin-10 Mitigates Doxorubicin-Induced Endoplasmic Reticulum Stress as Well as Cardiomyopathy |
| title_full | Interleukin-10 Mitigates Doxorubicin-Induced Endoplasmic Reticulum Stress as Well as Cardiomyopathy |
| title_fullStr | Interleukin-10 Mitigates Doxorubicin-Induced Endoplasmic Reticulum Stress as Well as Cardiomyopathy |
| title_full_unstemmed | Interleukin-10 Mitigates Doxorubicin-Induced Endoplasmic Reticulum Stress as Well as Cardiomyopathy |
| title_short | Interleukin-10 Mitigates Doxorubicin-Induced Endoplasmic Reticulum Stress as Well as Cardiomyopathy |
| title_sort | interleukin 10 mitigates doxorubicin induced endoplasmic reticulum stress as well as cardiomyopathy |
| topic | doxorubicin-induced cardiomyopathy interleukin-10 activating transcription factor 6α endoplasmic reticulum stress-induced apoptosis |
| url | https://www.mdpi.com/2227-9059/10/4/890 |
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