Dataset Information

Myocardial oxidative stress contributes to transgenic ??-adrenoceptor activation-induced cardiomyopathy and heart failure.

ABSTRACT:

Background and purpose

While maintaining cardiac performance, chronic ?-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 ??-adrenoceptor activation.

Experimental approach

Mice with transgenic ??-adrenoceptor overexpression (??-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.

Key results

??-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. ??-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 ??-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 ??-TG mice. Chronic NAC treatment to ??-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.

Conclusion and implications

??-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.

SUBMITTER: Xu Q

PROVIDER: S-EPMC3051376 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Myocardial oxidative stress contributes to transgenic β₂-adrenoceptor activation-induced cardiomyopathy and heart failure.

Xu Q Q Dalic A A Fang L L Kiriazis H H Ritchie R H RH Sim K K Gao X-M XM Drummond G G Sarwar M M Zhang Y-Y YY Dart A M AM Du X-J XJ

British journal of pharmacology 20110301 5

<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>Mice with transgenic β₂-adrenoceptor overexpression (β₂-TG) and non-transgenic littermates were eith ...[more]

PMID: 20955367

Similar Datasets

Project description:Cellular redox control is maintained by generation of reactive oxygen/nitrogen species balanced by activation of antioxidative pathways. Disruption of redox balance leads to oxidative stress, a central causative event in numerous diseases including heart failure. Redox control in the heart exposed to hemodynamic stress, however, remains to be fully elucidated. Here, we show that production of cardiomyocyte NADPH (nicotinamide adenine dinucleotide phosphate), a key factor in redox regulation, is decreased in pressure overload-induced heart failure. As a consequence, the level of reduced glutathione is downregulated, a change associated with cardiac cell death, fibrosis, and cardiomyopathy. We report that the pentose phosphate pathway (PPP) and mitochondrial serine/glycine/folate metabolic signaling, two major NADPH-generating pathways in the cytosol and mitochondria, respectively, are induced in the heart by pressure overload. We identify ATF4 (activating transcriptional factor 4) as an upstream transcription factor controlling the expression of multiple enzymes in these two pathways. Consistent with this, joint pathway analysis (JPA) of transcriptomic and metabolomic data reveals that ATF4 preferably controls oxidative stress and redox-related pathways. Overexpression of ATF4 in cardiomyocytes in culture leads to a significant increase in NADPH-producing enzymes whereas silencing of ATF4 decreases their expression. Further, stable isotope tracer experiments reveal that ATF4 overexpression in vitro strongly augments metabolic flux within these two pathways. In vivo, cardiomyocyte-specific deletion of ATF4 exacerbates cardiomyopathy in the setting of pressure overload and accelerates the development of heart failure, attributable, at least in part, to an inability to increase the expression of NADPH-generating enzymes. Taken together, our findings reveal that ATF4 plays a critical role in cardiac homeostasis under conditions of hemodynamic stress by governing both cytosolic and mitochondrial production of NADPH.