ABSTRACT
Interleukin-33 (IL-33), a new member of the IL-1 cytokine family, has cardiac protective effect in many circumstances. The aims of present study are to assess whether IL-33 can protect cardiomyocytes from doxorubicin (DOX)-induced apoptosis and the mechanism involved in the protection. Cardiomyocytes derived from either wild-type or c-Jun N-terminal kinase deficient (JNK-/-) mice were challenged with DOX (1 µM) with or without IL-33 (10 ng/ml). Myocyte apoptosis was assessed by measuring Caspase 3 activity, fragmented DNA and the TUNEL staining. In addition, cardiomyocyte reactive oxygen species (ROS) was assessed by measuring 2',7'-dichlorofluorescin diacetate (DCFDA); apoptosis signal-regulating kinase 1(ASK1) and JNK phosphorylation were assessed with western blot analysis. Treatment of cardiomyocyes with DOX resulted in ROS generation, ASK1 and JNK phosphorylation and myocyte apoptosis. IL-33 inhibited the DOX-induced ROS, prevented ASK1 and JNK phosphorylation and attenuated the DOX-induced myocyte apoptosis. Genetic inhibition of ASK1 (ASK1 siRNA transfection) and JNK (JNK-/-) ameliorated the cardiac-protective effect of IL-33. Moreover, inhibition of ASK1 prevented the DOX-induced phosphorylation of JNK, while inhibition of JNK showed no effect on DOX-induced ASK1 phosphorylation. Our study indicates that: 1) ASK1/JNK signaling pathway is involved in DOX-induced cardiomyocyte apoptosis; 2) IL-33 protects cardiomyocytes from DOX-induced myocyte apoptosis through inhibition of the ASK1/JNK signaling pathway. IL-33 may have therapeutic potential for DOX-induced cardiac injury.
Subject(s)
Doxorubicin/adverse effects , Interleukin-33/pharmacology , MAP Kinase Kinase 4/metabolism , MAP Kinase Kinase Kinase 5/metabolism , Myocytes, Cardiac/drug effects , Animals , Apoptosis/drug effects , Cells, Cultured , MAP Kinase Kinase Kinase 5/genetics , Mice, Inbred C57BL , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Oxidative Stress/drug effects , Phosphorylation/drug effects , Reactive Oxygen Species/metabolism , Signal Transduction/drug effectsABSTRACT
Previous studies have suggested that galectin-3 is an important mediator of cardiac fibrosis. The aim of this study was to investigate the utility of galectin-3 in identifying early left ventricular remodeling (LVRM) in patients with hypertension. A total of 107 patients with hypertension and 108 controls were enrolled in this study. The levels of galectin-3 were significantly greater in hypertension patients with LVRM compared with those without LVRM. Multivariate regression analysis demonstrated that body mass index and galectin-3 were independent predictors of LVRM in the hypertension group. Only left ventricular mass was independently correlated with serum galectin-3 levels in patients with hypertension. The receiver operating characteristic analysis showed an area under the curve for galectin-3 of 0.698 (P<.001), with an optimal cutoff of 9.43 ng/mL. Therefore, galectin-3 is independently correlated with LVRM and can be regarded as a valuable biomarker of early cardiac remodeling of hypertension.