Sodium-Glucose Co-Transporter-2 Inhibitor Empagliflozin Attenuates Sorafenib-Induced Myocardial Inflammation and Toxicity

被引：2

作者：

Liu C.-H. ^{[1
,2
,3
]}

Ho Y.-C. ^{[4
]}

Lee W.-C. ^{[5
]}

Huang C.-Y. ^{[6
]}

Lee Y.-K. ^{[7
,8
]}

Hsieh C.-B. ^{[9
]}

Huang N.-C. ^{[10
]}

Wu C.-C. ^{[4
]}

Nguyen N. ^{[11
]}

Hsu C.-C. ^{[11
]}

Chen C.-H. ^{[12
]}

Chen Y.-C. ^{[13
]}

Huang W.-C. ^{[14
]}

Lu Y.-Y. ^{[15
,16
]}

Fang C.-C. ^{[7
]}

Chang Y.-C. ^{[7
]}

Chang C.-L. ^{[8
,17
]}

Tsai M.-K. ^{[8
,18
]}

Wen Z.-H. ^{[3
]}

Li C.-Z. ^{[3
,19
]}

Li C.-C. ^{[3
,20
]}

Chuang P.-K. ^{[21
]}

Yang S.-M. ^{[21
]}

Chu T.-H. ^{[7
,8
]}

Huang S.-C. ^{[1
,2
,8
,22
]}

机构：

[1] Department of Internal Medicine, Division of Cardiology, Kaohsiung Armed Forces General Hospital, Kaohsiung

[2] Department of Internal Medicine, Division of Cardiology, Tri-Service General Hospital, National Defense Medical Center, Taipei

[3] Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung

[4] School of Medicine, Medical College, I-Shou University, Kaohsiung

[5] Department of Internal Medicine, Division of Nephrology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung

[6] Department of Pathology, Kaohsiung Armed Forces General Hospital, Kaohsiung

[7] Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, Kaohsiung

[8] Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung

[9] Division of General Surgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung

[10] Division of Family Medicine, Zuoying Armed Forces General Hospital, Kaohsiung

[11] Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, TX

[12] Biobank and Tissue Bank, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung

[13] Department of Biomedical Engineering, National Defense Medical Center, Taipei

[14] Department of Critical Care Medicine, Kaohsiung Veterans General Hospital, Kaohsiung

[15] Division of Cardiology, Sijhih Cathay General Hospital, New Taipei City

[16] School of Medicine, Fu-Jen Catholic University, New Taipei City

[17] Department of Psychiatry, Kaohsiung Armed Forces General Hospital, Kaohsiung

[18] Division of Nephrology, Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung

[19] Department of Surgery, Division of Neurosurgery, Kaohsiung Armed Forces General Hospital, Kaohsiung

[20] Department of Surgery, Division of Urology, Kaohsiung Armed Forces General Hospital, Kaohsiung

[21] Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung

[22] Department of Internal Medicine, Division of Cardiology, Pingtung Branch of Kaohsiung Armed Forces General Hospital, Pingtung

来源：

Environmental Toxicology | 2024年 / 39卷 / 11期

关键词：

empagliflozin; ferroptosis; proinflammatory signaling; sodium-glucose co-transporter-2 inhibitor; sorafenib cardiotoxicity;

D O I：

10.1002/tox.24362

中图分类号：

学科分类号：

摘要：

Environmental antineoplastics such as sorafenib may pose a risk to humans through water recycling, and the increased risk of cardiotoxicity is a clinical issue in sorafenib users. Thus, developing strategies to prevent sorafenib cardiotoxicity is an urgent work. Empagliflozin, as a sodium-glucose co-transporter-2 (SGLT2) inhibitor for type 2 diabetes control, has been approved for heart failure therapy. Still, its cardioprotective effect in the experimental model of sorafenib cardiotoxicity has not yet been reported. Real-time quantitative RT-PCR (qRT-PCR), immunoblot, and immunohistochemical analyses were applied to study the effect of sorafenib exposure on cardiac SGLT2 expression. The impact of empagliflozin on cell viability was investigated in the sorafenib-treated cardiomyocytes using Alamar blue assay. Immunoblot analysis was employed to delineate the effect of sorafenib and empagliflozin on ferroptosis/proinflammatory signaling in cardiomyocytes. Ferroptosis/DNA damage/fibrosis/inflammation of myocardial tissues was studied in mice with a 28-day sorafenib ± empagliflozin treatment using histological analyses. Sorafenib exposure significantly promoted SGLT2 upregulation in cardiomyocytes and mouse hearts. Empagliflozin treatment significantly attenuated the sorafenib-induced cytotoxicity/DNA damage/fibrosis in cardiomyocytes and mouse hearts. Moreover, GPX4/xCT-dependent ferroptosis as an inducer for releasing high mobility group box 1 (HMGB1) was also blocked by empagliflozin administration in the sorafenib-treated cardiomyocytes and myocardial tissues. Furthermore, empagliflozin treatment significantly inhibited the sorafenib-promoted NFκB/HMGB1 axis in cardiomyocytes and myocardial tissues, and sorafenib-stimulated proinflammatory signaling (TNF-α/IL-1β/IL-6) was repressed by empagliflozin administration. Finally, empagliflozin treatment significantly attenuated the sorafenib-promoted macrophage recruitments in mouse hearts. In conclusion, empagliflozin may act as a cardioprotective agent for humans under sorafenib exposure by modulating ferroptosis/DNA damage/fibrosis/inflammation. However, further clinical evidence is required to support this preclinical finding. © 2024 Wiley Periodicals LLC.

引用

页码：4844 / 4858

页数：14

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