Extracellular Vesicles Released after Doxorubicin Treatment in Rats Protect Cardiomyocytes from Oxidative Damage and Induce Pro-Inflammatory Gene Expression in Macrophages

被引：5

作者：

Yarana, Chontida ^{[1
]}

Siwaponanan, Panjaree ^{[2
]}

Maneechote, Chayodom ^{[3
,4
,5
]}

Khuanjing, Thawatchai ^{[3
,4
,5
]}

Ongnok, Benjamin ^{[3
,4
,5
]}

Prathumsap, Nanthip ^{[3
,4
,5
]}

Chattipakorn, Siriporn C. ^{[3
,5
,6
]}

Chattipakorn, Nipon ^{[3
,4
,5
]}

Pattanapanyasat, Kovit ^{[2
,7
]}

机构：

[1] Mahidol Univ, Fac Med Technol, Ctr Res & Innovat, 999 Phuttamonthon 4 Rd, Salaya 73170, Nakhon Pathom, Thailand

[2] Mahidol Univ, Fac Med, Ctr Excellence Microparticle & Exosome Dis, Dept Res & Dev,Siriraj Hosp, Bangkok 10700, Thailand

[3] Chiang Mai Univ, Fac Med, Cardiac Electrophysiol Res & Training Ctr, Chiang Mai 50200, Thailand

[4] Chiang Mai Univ, Fac Med, Dept Physiol, Cardiac Electrophysiol Unit, Chiang Mai 50200, Thailand

[5] Chiang Mai Univ, Ctr Excellence Cardiac Electrophysiol Res, Chiang Mai 50200, Thailand

[6] Chiang Mai Univ, Fac Dent, Dept Oral Biol & Diagnost Sci, Chiang Mai 50200, Thailand

[7] Mahidol Univ, Fac Med, Dept Immunol, Grad Program Immunol,Siriraj Hosp, Bangkok 10700, Thailand

来源：

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES | 2022年 / 23卷 / 21期

关键词：

doxorubicin; cardiotoxicity; extracellular vesicle; oxidative stress; macrophage; INDUCED CARDIOMYOPATHY; HYDROGEN-PEROXIDE; CANCER; BIOMARKERS; GROWTH; GENERATION; TOXICITY; INJURY;

D O I：

10.3390/ijms232113465

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Doxorubicin (DOXO)-induced cardiomyopathy (DIC) is a lethal complication in cancer patients. Major mechanisms of DIC involve oxidative stress in cardiomyocytes and hyperactivated immune response. Extracellular vesicles (EVs) mediate cell-cell communication during oxidative stress. However, functions of circulating EVs released after chronic DOXO exposure on cardiomyocytes and immune cells are still obscured. Herein, we developed a DIC in vivo model using male Wistar rats injected with 3 mg/kg DOXO for 6 doses within 30 days (18 mg/kg cumulative dose). One month after the last injection, the rats developed cardiotoxicity evidenced by increased BCL2-associated X protein and cleaved caspase-3 in heart tissues, along with N-terminal pro B-type natriuretic peptide in sera. Serum EVs were isolated by size exclusion chromatography. EV functions on H9c2 cardiomyocytes and NR8383 macrophages were evaluated. EVs from DOXO-treated rats (DOXO_EVs) attenuated ROS production via increased glutathione peroxidase-1 and catalase gene expression, and reduced hydrogen peroxide-induced cell death in cardiomyocytes. In contrast, DOXO_EVs induced ROS production, interleukin-6, and tumor necrosis factor-alpha, while suppressing arginase-1 gene expression in macrophages. These results suggested the pleiotropic roles of EVs against DIC, which highlight the potential role of EV-based therapy for DIC with a concern of its adverse effect on immune response.

引用

页数：17