Myocardial oxidative stress contributes to transgenic β2‐adrenoceptor activation‐induced cardiomyopathy and heart failure
- 28 January 2011
- journal article
- Published by Wiley in British Journal of Pharmacology
- Vol. 162 (5), 1012-1028
- https://doi.org/10.1111/j.1476-5381.2010.01043.x
Abstract
While maintaining cardiac performance, chronic β-adrenoceptor activation eventually exacerbates the progression of cardiac remodelling and failure. We examined the adverse signalling pathways mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and reactive oxygen species (ROS) after chronic β₂-adrenoceptor activation. Mice with transgenic β₂-adrenoceptor overexpression (β₂-TG) and non-transgenic littermates were either untreated or treated with an antioxidant (N-acetylcysteine, NAC) or NADPH oxidase inhibitors (apocynin, diphenyliodonium). Levels of ROS, phosphorylated p38 mitogen-activated protein kinase (MAPK), pro-inflammatory cytokines and collagen content in the left ventricle (LV) and LV function were measured and compared. β₂-TG mice showed increased ROS production, phosphorylation of p38 MAPK and heat shock protein 27 (HSP27), expression of pro-inflammatory cytokines and collagen, and progressive ventricular dysfunction. β₂-adrenoceptor stimulation similarly increased ROS production and phosphorylation of p38 MAPK and HSP27 in cultured cardiomyocytes. Treatment with apocynin, diphenyliodonium or NAC reduced phosphorylation of p38 MAPK and HSP27 in both cultured cardiomyocytes and the LV of β₂-TG mice. NAC treatment (500 mg·kg⁻¹ ·day⁻¹) for 2 weeks eliminated the up-regulated expression of pro-inflammatory cytokines and collagen in the LV of β₂-TG mice. Chronic NAC treatment to β₂-TG mice from 7 to 10 months of age largely prevented progression of ventricular dilatation, preserved contractile function (fractional shortening 37 ± 5% vs. 25 ± 3%, ejection fraction 52 ± 5% vs. 32 ± 4%, both P < 0.05), reduced cardiac fibrosis and suppressed matrix metalloproteinase activity. β₂-adrenoceptor stimulation provoked NADPH oxidase-derived ROS production in the heart. Elevated ROS activated p38 MAPK and contributed significantly to cardiac inflammation, remodelling and failure.This publication has 50 references indexed in Scilit:
- Guide to Receptors and Channels (GRAC), 4th editionBritish Journal of Pharmacology, 2009
- NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injuryNature Medicine, 2009
- β-Arrestin Mediates β1-Adrenergic Receptor-Epidermal Growth Factor Receptor Interaction and Downstream SignalingOnline Journal of Public Health Informatics, 2009
- Hematopoietic Protein Tyrosine Phosphatase Mediates β2-Adrenergic Receptor-Induced Regulation of p38 Mitogen-Activated Protein Kinase in B LymphocytesMolecular and Cellular Biology, 2009
- A Novel Protein Kinase A-independent, β-Arrestin-1-dependent Signaling Pathway for p38 Mitogen-activated Protein Kinase Activation by β2-Adrenergic ReceptorsOnline Journal of Public Health Informatics, 2008
- TNF-α upregulates the A2B adenosine receptor gene: The role of NAD(P)H oxidase 4Biochemical and Biophysical Research Communications, 2008
- Measurement of cardiac function using pressure–volume conductance catheter technique in mice and ratsNature Protocols, 2008
- Mechanisms of Disease: detrimental adrenergic signaling in acute decompensated heart failureNature Clinical Practice Cardiovascular Medicine, 2008
- Knockout of β1‐ and β2‐adrenoceptors attenuates pressure overload‐induced cardiac hypertrophy and fibrosisBritish Journal of Pharmacology, 2008
- Inhibition of p38α MAPK rescues cardiomyopathy induced by overexpressed β2-adrenergic receptor, but not β1-adrenergic receptorJCI Insight, 2007