RETRACTED ARTICLE: Role of aminolevulinic acid synthase 1 in doxorubicin-induced oxidative stress to the ardiomyocyte
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ORIGINAL ARTICLE
Role of aminolevulinic acid synthase 1 in doxorubicin-induced oxidative stress to the ardiomyocyte Zuoyan Wang 1 & Junyi Gao 1 & Haobo Teng 1 & Jianjun Peng 1 Received: 24 June 2019 / Accepted: 19 December 2019 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Aminolevulinic acid synthase 1(ALAS 1) is the rate-limiting enzyme for heme synthesis, which is the essential source of intracellular oxidative stress under specific conditions. This study aimed to identify the role of ALAS1 in the oxidative injury of cardiomyocyte induced by doxorubicin. H9c2 cardiac myocytes were treated with a 5-μM concentration of doxorubicin for 24 h. ALAS1 small interfering RNA (siRNA) or rALAS1 plasmid was transfected into H9c2 cardiac myocytes to establish ALAS1 knockdown or over-expressing H9c2 cells. Apoptotic cells were detected using flow cytometric analysis. ALAS1 expression was detected by real-time PCR and western blot assay. The levels of heme were detected by ELISA. MitoSOX Red was introduced for detection of mitochondrial superoxide in H9c2 cells and was validated with confocal fluorescence microscopy. Doxorubicin increase the expression of ALAS1, and heme promotes the oxidative stress and apoptosis in H9c2 cardiac myocytes. Over-expression of ALAS1 can produce similar apoptotic effect on H9c2 cells with doxorubicin, although at a relatively low level. Inhibition of ALAS1 by ALAS1 siRNA decreased heme and mitochondrial superoxide levels, results in inhibition of doxorubicin-induced apoptosis. ALAS1 plays a pivotal role in the doxorubicin-induced oxidative stress and apoptosis in H9c2 cardiac myocytes. Keywords Doxorubicin . Aminolevulinic acid synthase . Heme . Cardiomyocyte . Oxidative stress
Introduction With the continuing progression of anti-cancer drug radiation therapy, survival rates of patients with cancer have been improving from decade to decade, and their life expectancy has increased substantially. However, the widespread use of anticancer drugs in chemotherapy is associated with an increased risk of developing adverse cardiovascular events, which affects the quality of life and survival in cancer patients. Anthracyclines, including doxorubicin and epirubicin, are drugs derived from streptomycin and widely used to treat breast cancer, small cell lung cancer, myeloma, sarcoma, lymphoma, and leukemia (Mordente et al. 2017). The cardiovascular toxicity of anthracyclines is cumulative dose-dependent
* Jianjun Peng [email protected] 1
Department of Cardiology, Beijing Shijitan Hospital, Capital Medical University, No.10 Tieyi Road, Haidian District, Beijing 100038, China
and may potentially cause cardiomyocyte damage, mayocardiopathy, and subsequent heart failure (Mordente et al. 2017; Patanè 2014). The exact mechanism of anthracycline drug-induced myocardial toxicity remains unclear, though a variety of theories have been proposed, including the inhibition of DNA replication and RNA transcription, DNA damage caused by free radicals, lipid peroxidation and alkylation, DNA cross
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