Involvement of Nuclear Factor-κB and Apoptosis Signal-Regulating Kinase 1 in G-Protein–Coupled Receptor Agonist–Induced Cardiomyocyte Hypertrophy
- 29 January 2002
- journal article
- other
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation
- Vol. 105 (4), 509-515
- https://doi.org/10.1161/hc0402.102863
Abstract
Background — Recently, reactive oxygen species (ROS) have emerged as important molecules in cardiac hypertrophy. However, the ROS-dependent signal transduction mechanism remains to be elucidated. In this study, we examined the role of an ROS-sensitive transcriptional factor, NF-κB, and a mitogen-activated protein kinase kinase kinase, apoptosis signal-regulating kinase 1 (ASK1), in G-protein–coupled receptor (GPCR) agonist (angiotensin II, endothelin-1, phenylephrine)-induced cardiac hypertrophy in isolated rat neonatal cardiomyocytes. Methods and Results — Using an ROS-sensitive fluorescent dye, we observed an increase in fluorescence signal on addition of the GPCR agonists. The GPCR agonists induced NF-κB activation. Antioxidants such as N -acetyl cysteine, N -mercaptopropionyl glycine, and vitamin E attenuated the NF-κB activation. Infection of cardiomyocytes with an adenovirus expressing a degradation-resistant mutant of IκBα led to suppression of the hypertrophic responses. The GPCR agonists rapidly and transiently activated ASK1 in a dose-dependent manner. Infection of an adenovirus expressing a dominant-negative ASK1 attenuated the GPCR agonist–induced NF-κB activation and cardiac hypertrophy. Overexpression of a constitutively active mutant of ASK1 led to NF-κB activation and cardiac hypertrophy. Activated ASK1-induced hypertrophy was abolished by inhibition of NF-κB activation. Conclusions — These data indicate that GPCR agonist–induced cardiac hypertrophy is mediated through NF-κB activation via the generation of ROS. ASK1 is involved in GPCR agonist–induced NF-κB activation and resulting hypertrophy.This publication has 15 references indexed in Scilit:
- Apoptosis Signal-regulating Kinase 1 (ASK1) Induces Neuronal Differentiation and Survival of PC12 CellsOnline Journal of Public Health Informatics, 2000
- Mechanical strain activates BNP gene transcription through a p38/NF-κB–dependent mechanismJCI Insight, 1999
- Role of redox potential and reactive oxygen species in stress signalingOncogene, 1999
- The kinase TAK1 can activate the NIK-IκB as well as the MAP kinase cascade in the IL-1 signalling pathwayNature, 1999
- Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1The EMBO Journal, 1998
- MKK6 Activates Myocardial Cell NF-κB and Inhibits Apoptosis in a p38 Mitogen-activated Protein Kinase-dependent MannerOnline Journal of Public Health Informatics, 1998
- The MEKK-JNK Pathway Is Stimulated by α1-Adrenergic Receptor and Ras Activation and Is Associated with in Vitro and in Vivo Cardiac HypertrophyOnline Journal of Public Health Informatics, 1997
- Induction of Apoptosis by ASK1, a Mammalian MAPKKK That Activates SAPK/JNK and p38 Signaling PathwaysScience, 1997
- p22 Is a Critical Component of the Superoxide-generating NADH/NADPH Oxidase System and Regulates Angiotensin IIinduced Hypertrophy in Vascular Smooth Muscle CellsJournal of Biological Chemistry, 1996
- Thyroid Hormone Enhances Ca2+ Pumping Activity of the Cardiac Sarcoplasmic Reticulum by Increasing Ca2+ ATPase and Decreasing Phospholamban ExpressionJournal of Molecular and Cellular Cardiology, 1994