Dipendra Khadka1, Hyung-Jin Kim1, Gi-Su Oh1, AiHua Shen1, SeungHoon Lee1, Su-Bin Lee1, Subham Sharma1, Seon Young Kim1, Arpana Pandit1, Seong-Kyu Choe1, Tae Hwan Kwak1, Sei-Hoon Yang2, Hyuk Sim2, Gwang Hyeon Eom3, Raekil Park4, Hong-Seob So5. 1. Center for Metabolic Function Regulation, & Department of Microbiology, Republic of Korea. 2. Internal Medicine, School of Medicine Wonkwang, University School of Medicine, Iksan, Jeonbuk 54538, Republic of Korea. 3. Department of Pharmacology, Medical Research Center for Gene Regulation Chonnam, National University Medical School, Hwasungun Jeollanam-do 58128, Republic of Korea. 4. Department of Biomedical Science & Engineering, Institute of Integrated Technology, Gwangju Institute of Science and Technology, Gwangju 61005, Republic of Korea. 5. Center for Metabolic Function Regulation, & Department of Microbiology, Republic of Korea.. Electronic address: jeanso@wku.ac.kr.
Abstract
BACKGROUND: Adriamycin (ADR) is a powerful chemotherapeutic agent extensively used to treat various human neoplasms. However, its clinical utility is hampered due to severe adverse side effects i.e. cardiotoxicity and heart failure. ADR-induced cardiomyopathy (AIC) has been reported to be caused by myocardial damage and dysfunction through oxidative stress, DNA damage, and inflammatory responses. Nonetheless, the remedies for AIC are even not established. Therefore, we illustrate the role of NAD+/NADH modulation by NAD(P)H quinone oxidoreductase 1 (NQO1) enzymatic action on AIC. METHODS AND RESULTS: AIC was established by intraperitoneal injection of ADR in C57BL/6 wild-type (WT) and NQO1 knockout (NQO1-/-) mice. All Mice were orally administered dunnione (named NQO1 substrate) before and after exposure to ADR. Cardiac biomarker levels in the plasma, cardiac dysfunction, oxidative biomarkers, and mRNA and protein levels of pro-inflammatory mediators were determined compared the cardiac toxicity of each experimental group. All biomarkers of Cardiac damage and oxidative stress, and mRNA levels of pro-inflammatory cytokines including cardiac dysfunction were increased in ADR-treated both WT and NQO1-/- mice. However, this increase was significantly reduced by dunnione in WT, but not in NQO1-/- mice. In addition, a decrease in SIRT1 activity due to a reduction in the NAD+/NADH ratio by PARP-1 hyperactivation was associated with AIC through increased nuclear factor (NF)-κB p65 and p53 acetylation in both WT and NQO1-/- mice. While an elevation in NAD+/NADH ratio via NQO1 enzymatic action using dunnione recovered SIRT1 activity and subsequently deacetylated NF-κB p65 and p53, however not in NQO1-/- mice, thereby attenuating AIC. CONCLUSION: Thus, modulation of NAD+/NADH by NQO1 may be a novel therapeutic approach to prevent chemotherapy-associated heart failure, including AIC.
BACKGROUND:Adriamycin (ADR) is a powerful chemotherapeutic agent extensively used to treat various humanneoplasms. However, its clinical utility is hampered due to severe adverse side effects i.e. cardiotoxicity and heart failure. ADR-induced cardiomyopathy (AIC) has been reported to be caused by myocardial damage and dysfunction through oxidative stress, DNA damage, and inflammatory responses. Nonetheless, the remedies for AIC are even not established. Therefore, we illustrate the role of NAD+/NADH modulation by NAD(P)H quinone oxidoreductase 1 (NQO1) enzymatic action on AIC. METHODS AND RESULTS: AIC was established by intraperitoneal injection of ADR in C57BL/6 wild-type (WT) and NQO1 knockout (NQO1-/-) mice. All Mice were orally administered dunnione (named NQO1 substrate) before and after exposure to ADR. Cardiac biomarker levels in the plasma, cardiac dysfunction, oxidative biomarkers, and mRNA and protein levels of pro-inflammatory mediators were determined compared the cardiac toxicity of each experimental group. All biomarkers of Cardiac damage and oxidative stress, and mRNA levels of pro-inflammatory cytokines including cardiac dysfunction were increased in ADR-treated both WT and NQO1-/- mice. However, this increase was significantly reduced by dunnione in WT, but not in NQO1-/- mice. In addition, a decrease in SIRT1 activity due to a reduction in the NAD+/NADH ratio by PARP-1 hyperactivation was associated with AIC through increased nuclear factor (NF)-κB p65 and p53 acetylation in both WT and NQO1-/- mice. While an elevation in NAD+/NADH ratio via NQO1 enzymatic action using dunnione recovered SIRT1 activity and subsequently deacetylated NF-κB p65 and p53, however not in NQO1-/- mice, thereby attenuating AIC. CONCLUSION: Thus, modulation of NAD+/NADH by NQO1 may be a novel therapeutic approach to prevent chemotherapy-associated heart failure, including AIC.