title: ALDH2 attenuates Dox-induced cardiotoxicity by inhibiting cardiac apoptosis and oxidative stress.
abstract: The anthracycline chemotherapy drug doxorubicin (DOX) is cardiotoxic. This study aimed to explore the effect of acetaldehyde dehydrogenase 2 (ALDH2), a detoxifying protein, on DOX-induced cardiotoxicity and unveil the underlying mechanisms. BALB/c mice were randomly divided in four groups: control group (no treatment), DOX group (DOX administration for myocardial damage induction), DOX + Daidzin group (DOX administration + Daidzin, an ALDH2 antagonist) and DOX + Alda-1 group (DOX administration + Alda-1, an ALDH2 agonist). Then, survival, haemodynamic parameters, expression of pro- and anti-apoptosis markers, reactive oxygen species (ROS) and 4-Hydroxynonenal (4-HNE) levels, expression and localization of NADPH oxidase 2 (NOX2) and its cytoplasmic subunit p47(PHOX), and ALDH2 expression and activity were assessed. Mortality rates of 0, 35, 5, and 70% were obtained in the control, DOX, DOX + Alda-1, and DOX + Daidzin groups, respectively, at the ninth weekend. Compared with control animals, DOX treatment resulted in significantly reduced left ventricular systolic pressure (LVSP) and ± dp/dt, and overtly increased left ventricular end-diastolic pressure (LVEDP); increased Bax expression and caspase-3/7 activity, and reduced Bcl-2 expression in the myocardium; increased ROS (about 2 fold) and 4-HNE adduct (3 fold) levels in the myocardium; increased NOX2 protein expression and membrane translocation of P47(PHOX). These effects were aggravated in the DOX + Daidzin group, DOX + Alda-1 treated animals showed partial or complete alleviation. Finally, Daidzin further reduced the DOX-repressed ALDH2 activity, which was partially rescued by Alda-1. These results indicated that ALDH2 attenuates DOX-induced cardiotoxicity by inhibiting oxidative stress, NOX2 expression and activity, and reducing myocardial apoptosis.
authors.affiliation: Department of Gerontology, The Second Xiangya Hospital, Central South University Changsha 410011, China.
authors.forename: Yawen
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Gerontology, The Second Xiangya Hospital, Central South University Changsha 410011, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: General Surgery Department, The Second Xiangya Hospital, Central South University Changsha 410011, China.
authors.forename: Songwen
authors.initials: S
authors.lastname: Hua
authors.affiliation: Deparment of Vasculocardiology, The Second Xiangya Hospital, Central South University Changsha 410011, China.
authors.forename: Shenghua
authors.initials: S
authors.lastname: Zhou
authors.affiliation: Department of Pathophysiology, Xiangya School of Medicine, Central South University Changsha 410011, China.
authors.forename: Kangkai
authors.initials: K
authors.lastname: Wang
keywords: ALDH2; DOX; NOX2; myocardial apoptosis; oxidative stress