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学科主题: 临床医学
题名:
Myocardial oxidative stress contributes to transgenic beta(2)-adrenoceptor activation-induced cardiomyopathy and heart failure
作者: Xu, Q.1; Dalic, A.1; Fang, L.1; Kiriazis, H.1; Ritchie, R. H.1,2; Sim, K.1; Gao, X-M1,2; Drummond, G.3; Sarwar, M.3; Zhang, Y-Y4,5; Dart, A. M.2,6; Du, X-J1,2
关键词: beta-adrenoceptor ; reactive oxygen species ; NADPH oxidase ; p38 MAPK ; heart failure ; cardiomyopathy ; inflammation ; fibrosis
刊名: BRITISH JOURNAL OF PHARMACOLOGY
发表日期: 2011-03-01
DOI: 10.1111/j.1476-5381.2010.01043.x
卷: 162, 期:5, 页:1012-1028
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Pharmacology & Pharmacy
研究领域[WOS]: Pharmacology & Pharmacy
关键词[WOS]: INDUCED CARDIAC-HYPERTROPHY ; PROTEIN-KINASE-A ; RECEPTOR OVEREXPRESSION ; DILATED CARDIOMYOPATHY ; PRESSURE-OVERLOAD ; BETA(1)-ADRENERGIC RECEPTOR ; BETA-2-ADRENERGIC RECEPTOR ; P38-ALPHA MAPK ; NADPH OXIDASE ; CELL-DEATH
英文摘要:

BACKGROUND AND PURPOSE

While maintaining cardiac performance, chronic beta-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 beta(2)-adrenoceptor activation.

EXPERIMENTAL APPROACH

Mice with transgenic beta(2)-adrenoceptor overexpression (beta(2)-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

beta(2)-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. beta(2)-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 beta(2)-TG mice. NAC treatment (500 mg center dot kg-1 center dot day-1) for 2 weeks eliminated the up-regulated expression of pro-inflammatory cytokines and collagen in the LV of beta(2)-TG mice. Chronic NAC treatment to beta(2)-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

beta(2)-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.

LINKED ARTICLE

This article is commented on by Di Lisa et al., pp. 1009-1011 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2010.01130.x.

语种: 英语
所属项目编号: 472600 ; G08M3760 ; 30910103902
项目资助者: National Health and Medical Research Council (NHMRC) of Australia ; National Heart Foundation of Australia ; Baker IDI Heart and Diabetes Institute ; Nature Science Fund of China
WOS记录号: WOS:000286668500002
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/62233
Appears in Collections:北京大学第三临床医学院_心血管内科_期刊论文

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作者单位: 1.Baker IDI Heart & Diabet Inst, Melbourne, Vic 8008, Australia
2.Monash Univ, Sch Med, Melbourne, Vic 3004, Australia
3.Monash Univ, Dept Pharmacol, Melbourne, Vic 3004, Australia
4.Peking Univ, Hosp 3, Inst Vasc Med, Beijing 100871, Peoples R China
5.Chinese Minist Educ, Key Lab Mol Cardiovasc Sci, Beijing, Peoples R China
6.Alfred Hosp, Alfred Heart Ctr, Melbourne, Vic, Australia

Recommended Citation:
Xu, Q.,Dalic, A.,Fang, L.,et al. Myocardial oxidative stress contributes to transgenic beta(2)-adrenoceptor activation-induced cardiomyopathy and heart failure[J]. BRITISH JOURNAL OF PHARMACOLOGY,2011,162(5):1012-1028.
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