OBJECTIVE: Sympathetic nervous system activity in the myocardium is increased in patients with heart failure. However, the in vivo mechanisms responsible for beta-adrenoceptor-mediated cardiac hypertrophy or remodeling remain unclear. This study aimed to clarify the role of reactive oxygen species (ROS) in mitogen-activated protein (MAP) kinase activation and tissue remodeling of the heart of isoproterenol (ISO)-infused rats. METHODS AND RESULTS: Different doses of ISO (up to 1000 ng/kg/min) were given intravenously to conscious rats for 30 min. Phosphorylated MAP kinase levels (ERK1/2, JNK, p38) and lipid peroxidation were measured in the cardiac left ventricle, revealing the dose-dependent augmentation of MAP kinase phosphorylation and increased lipid peroxidation levels. Simultaneous treatment with 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (Tempol), a membrane-permeable radical scavenger, completely eliminated the increases of phosphorylated MAP kinases and their upstream elements (Raf-1, Rac-1, ASK-1) as well as the increases of cardiac lipid peroxidation induced by the highest dose of ISO infusion. In chronically ISO-infused rats (3 mg/kg/day, s.c. for 10 days), cardiac hypertrophy developed with accompanying increases of collagen content, whereas cardiac phosphorylated MAP kinases returned to normal. Tempol treatment prevented increases of collagen accumulation and type I collagen mRNA without any significant reduction of cardiac mass enlargement induced by chronic ISO infusion. CONCLUSION: beta-Adrenoceptor stimulation provokes cardiac oxidative stress. In the acute phase of ISO infusion, ROS are important activators of cardiac MAP kinase cascades; while, in the chronic phase, ROS may participate in cardiac remodeling, especially in respect to wall stiffness, based on fibrogenesis.
OBJECTIVE: Sympathetic nervous system activity in the myocardium is increased in patients with heart failure. However, the in vivo mechanisms responsible for beta-adrenoceptor-mediated cardiac hypertrophy or remodeling remain unclear. This study aimed to clarify the role of reactive oxygen species (ROS) in mitogen-activated protein (MAP) kinase activation and tissue remodeling of the heart of isoproterenol (ISO)-infused rats. METHODS AND RESULTS: Different doses of ISO (up to 1000 ng/kg/min) were given intravenously to conscious rats for 30 min. Phosphorylated MAP kinase levels (ERK1/2, JNK, p38) and lipid peroxidation were measured in the cardiac left ventricle, revealing the dose-dependent augmentation of MAP kinase phosphorylation and increased lipid peroxidation levels. Simultaneous treatment with 4-hydroxy-2,2,6,6-tetramethyl piperidinoxyl (Tempol), a membrane-permeable radical scavenger, completely eliminated the increases of phosphorylated MAP kinases and their upstream elements (Raf-1, Rac-1, ASK-1) as well as the increases of cardiac lipid peroxidation induced by the highest dose of ISO infusion. In chronically ISO-infused rats (3 mg/kg/day, s.c. for 10 days), cardiac hypertrophy developed with accompanying increases of collagen content, whereas cardiac phosphorylated MAP kinases returned to normal. Tempol treatment prevented increases of collagen accumulation and type I collagen mRNA without any significant reduction of cardiac mass enlargement induced by chronic ISO infusion. CONCLUSION: beta-Adrenoceptor stimulation provokes cardiac oxidative stress. In the acute phase of ISO infusion, ROS are important activators of cardiac MAP kinase cascades; while, in the chronic phase, ROS may participate in cardiac remodeling, especially in respect to wall stiffness, based on fibrogenesis.
Authors: Kim N Ha; Larry R Masterson; Zhanjia Hou; Raffaello Verardi; Naomi Walsh; Gianluigi Veglia; Seth L Robia Journal: Proc Natl Acad Sci U S A Date: 2011-01-31 Impact factor: 11.205
Authors: A Salameh; H Djilali; K Blanke; J Gonzalez Casanova; S von Salisch; A Savtschenko; S Dhein; I Dähnert Journal: Naunyn Schmiedebergs Arch Pharmacol Date: 2013-03-03 Impact factor: 3.000
Authors: Lo Lai; Lin Yan; Shumin Gao; Che-Lin Hu; Hui Ge; Amy Davidow; Misun Park; Claudio Bravo; Kousaku Iwatsubo; Yoshihiro Ishikawa; Johan Auwerx; David A Sinclair; Stephen F Vatner; Dorothy E Vatner Journal: Circulation Date: 2013-03-27 Impact factor: 29.690