title: Docosahexaenoic Acid Attenuates Doxorubicin-induced Cytotoxicity and Inflammation by Suppressing NF-κB/iNOS/NO Signaling Pathway Activation in H9C2 Cardiac Cells.
abstract: Doxorubicin (DOX) is a widely used antineoplastic agent for a variety of carcinomas. However, it is cardiotoxic and leads to cardiomyopathy. Previous studies have indicated that omega-3 polyunsaturated acids (ω-3 PUFAs) have therapeutic effects on dilated and diabetic cardiomyopathies. However, whether ω-3 PUFAs exert therapeutic effects on DOX-induced cardiomyopathy remains unclear. In this study, we explored the effect and underlying mechanisms of docosahexaenoic acid (DHA), an important type of ω-3 PUFA, on DOX-induced cardiotoxicity and inflammation. H9C2 cardiac cells were exposed to DOX (5 μM) and interfered with by DHA (10 μM) for 4 hours. The effect of DHA on H9C2 cell viability was measured by Cell Counting Kit-8 assay. The levels of mRNA and protein expression of inflammatory cytokines were determined by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Reactive oxygen species and nitric oxide (NO) levels were determined by corresponding kits. The protein expression of key molecules in the nuclear factor-kappa B/inducible isoform of nitric oxide synthase/nitric oxide (NF-κB/iNOS/NO) signaling pathway was determined by western blotting. DOX-induced significant cytotoxicity and reactive oxygen species production in H9C2 cardiac cells. It also induced cardiac inflammation as evidenced by significantly increased expressions of inflammatory cytokines, including tumor necrosis factor-α, interleukin-6, interleukin-1β, monocyte chemoattractant protein-1, and inducible isoform of NO synthase. However, DHA effectively attenuated DOX-induced cytotoxicity and inflammation. A further mechanistic study revealed that DHA suppressed DOX-induced activation of the NF-κB/iNOS/NO signaling pathway in H9C2 cells. Our results indicate that DHA may protect against DOX-induced cardiotoxicity by inhibiting NF-κB/iNOS/NO signaling pathway activation.
authors.affiliation: Department of Cardiology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Zhi-Quan
authors.initials: ZQ
authors.lastname: Wang
authors.forename: Man-Tian
authors.initials: MT
authors.lastname: Chen
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Yi-Gang
authors.initials: YG
authors.lastname: Li
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D009202:Cardiomyopathies / Q000139:chemically induced / Q000517:prevention & control; D066126:Cardiotoxicity / Q000209:etiology / Q000517:prevention & control*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004317:Doxorubicin / Q000633:toxicity*; D004797:Enzyme-Linked Immunosorbent Assay; D007249:Inflammation / Q000517:prevention & control*; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D016207:Cytokines; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D004281:Docosahexaenoic Acids; D009569:Nitric Oxide; D004317:Doxorubicin; D052247:Nitric Oxide Synthase Type II