Huiquan Lou1, Kuljeet Kaur, Anita K Sharma, Pawan K Singal. 1. Institute of Cardiovascular Sciences, Department of Physiology, St. Boniface General Hospital Research Center, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
Abstract
BACKGROUND: Adriamycin (ADR) induced heart failure is associated with an increase in oxidative stress and apoptosis. Changes due to ADR in mitogen-activated protein kinases (ERK1/2 and p38 MAPKs), pro- and anti-apoptotic proteins (Bax and Bcl-xl) and apoptosis were examined in isolated adult rat cardiomyocytes. METHODS: Isolated adult rat cardiomyocytes were exposed to different concentrations of ADR (0.1, 1 and 10mumol/L) and analyzed at different post-treatment durations. Antioxidant, trolox (20mumol/L) was used to determine involvement of oxidative stress on these changes. RESULTS: Total ERK1/2 and p38 did not show any significant change. However, phosphorylated ERK1/2 showed a rapid increase (497%) after 5min of ADR treatment, peaking (610%) at 10min followed by a decline to submaximal levels at 30min (280%) and 60min (247%). Phosphorylated p38 showed no changes until after 30min, peaking (284%) at 1h, followed by a small decline at 2h. These changes were found to be dose-dependent (0.1, 1 and 10mumol/L of ADR). Adriamycin induced apoptosis was confirmed by Hoechst staining. The ratio of Bax/Bcl-xl increased in a dose-dependent manner. At 10mumol/L, this ratio increased to a maximum at 1h, remained steady at the level for up to 12h, followed by a decline below the base line at 24h. Antioxidant, trolox modulated the ADR-induced increase in phosphorylation of ERK1/2 and p38 MAPKs as well as in the ratio of Bax/Bcl-xl. CONCLUSION: It is suggested that ADR activates MAP kinases, followed by an activation of pro-apoptotic protein Bax which results in cardiomyocyte apoptosis and these effects appear to be mediated by ADR-induced oxidative stress.
BACKGROUND:Adriamycin (ADR) induced heart failure is associated with an increase in oxidative stress and apoptosis. Changes due to ADR in mitogen-activated protein kinases (ERK1/2 and p38 MAPKs), pro- and anti-apoptotic proteins (Bax and Bcl-xl) and apoptosis were examined in isolated adult rat cardiomyocytes. METHODS: Isolated adult rat cardiomyocytes were exposed to different concentrations of ADR (0.1, 1 and 10mumol/L) and analyzed at different post-treatment durations. Antioxidant, trolox (20mumol/L) was used to determine involvement of oxidative stress on these changes. RESULTS: Total ERK1/2 and p38 did not show any significant change. However, phosphorylated ERK1/2 showed a rapid increase (497%) after 5min of ADR treatment, peaking (610%) at 10min followed by a decline to submaximal levels at 30min (280%) and 60min (247%). Phosphorylated p38 showed no changes until after 30min, peaking (284%) at 1h, followed by a small decline at 2h. These changes were found to be dose-dependent (0.1, 1 and 10mumol/L of ADR). Adriamycin induced apoptosis was confirmed by Hoechst staining. The ratio of Bax/Bcl-xl increased in a dose-dependent manner. At 10mumol/L, this ratio increased to a maximum at 1h, remained steady at the level for up to 12h, followed by a decline below the base line at 24h. Antioxidant, trolox modulated the ADR-induced increase in phosphorylation of ERK1/2 and p38 MAPKs as well as in the ratio of Bax/Bcl-xl. CONCLUSION: It is suggested that ADR activates MAP kinases, followed by an activation of pro-apoptotic protein Bax which results in cardiomyocyte apoptosis and these effects appear to be mediated by ADR-induced oxidative stress.
Authors: T Simůnek; M Sterba; O Popelová; H Kaiserová; M Adamcová; M Hroch; P Hasková; P Ponka; V Gersl Journal: Br J Pharmacol Date: 2008-06-09 Impact factor: 8.739
Authors: Yunfang Zhang; Haitham El-Sikhry; Ketul R Chaudhary; Sri Nagarjun Batchu; Anooshirvan Shayeganpour; Taibeh Orujy Jukar; J Alyce Bradbury; Joan P Graves; Laura M DeGraff; Page Myers; Douglas C Rouse; Julie Foley; Abraham Nyska; Darryl C Zeldin; John M Seubert Journal: Am J Physiol Heart Circ Physiol Date: 2009-05-08 Impact factor: 4.733