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学科主题: 临床医学
题名:
Activation of alpha(1B)-adrenoceptors contributes to intermittent hypobaric hypoxia-improved postischemic myocardial performance via inhibiting MMP-2 activation
作者: Gao, Ling1,2; Chen, Le1,2; Lu, Zhi-Zhen3,4; Gao, Hong1,2; Wu, Lan1,2; Chen, Yi-Xiong1,2; Zhang, Cai-Mei1,2; Jiang, Yu-Kun1,2; Jing, Qing1,2; Zhang, You-Yi3,4; Yang, Huang-Tian1,2
关键词: intermittent hypobaric hypoxia ; ischemia-reperfusion injury ; matrix metalloenzymes-2 ; alpha(1)-adrenoceptors ; mitochondria
刊名: AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
发表日期: 2014-06-01
DOI: 10.1152/ajpheart.00772.2013
卷: 306, 期:11, 页:H1569-H1581
收录类别: SCI
文章类型: Article
WOS标题词: Science & Technology
类目[WOS]: Cardiac & Cardiovascular Systems ; Physiology ; Peripheral Vascular Disease
研究领域[WOS]: Cardiovascular System & Cardiology ; Physiology
关键词[WOS]: ISCHEMIA-REPERFUSION INJURY ; HIGH-ALTITUDE HYPOXIA ; PROTEIN-KINASE-C ; MATRIX METALLOPROTEINASE-2 ACTIVITY ; CA2+ OVERLOAD INJURY ; RAT HEARTS ; ISCHEMIA/REPERFUSION INJURY ; ALPHA(1)-ADRENERGIC RECEPTOR ; INDUCED CARDIOPROTECTION ; TISSUE INHIBITOR
英文摘要:

Inhibition of matrix metalloproteinases-2 (MMP-2) activation renders cardioprotection from ischemia/reperfusion (I/R) injury; however, the signaling pathways involved have not been fully understood. Intermittent hypobaric hypoxia (IHH) has been shown to enhance myocardial tolerance to I/R injury via triggering intrinsic adaptive responses. Here we investigated whether IHH protects the heart against I/R injury via the regulation of MMP-2 and how the MMP-2 is regulated. IHH (PO2 = 84 mmHg, 4-h/day, 4 wk) improved postischemic myocardial contractile performance, lactate dehydrogenase (LDH) release, and infarct size in isolated perfused rat hearts. Moreover, IHH reversed I/R-induced MMP-2 activation and release, disorders in the levels of MMP-2 regulators, peroxynitrite (ONOO-) and tissue inhibitor of metalloproteinase-4 (TIMP-4), and loss of the MMP-2 targets alpha-actinin and troponin I. This protection was mimicked, but not augmented, by a MMP inhibitor doxycycline and lost by the alpha(1)-adrenoceptor (AR) antagonist prazosin. Furthermore, IHH increased myocardial alpha(1A)-AR and alpha(1B)-AR density but not alpha(1D)-AR after I/R. Concomitantly, IHH further enhanced the translocation of PKC epsilon (PKC epsilon) and decreased the release of mitochondrial cytochrome c due to I/R via the activation of alpha(1B)-AR but not alpha(1A)-AR or alpha(1D)-AR. IHH-conferred cardioprotection in the postischemic contractile function, LDH release, MMP-2 activation, and nitrotyrosine as well as TIMP-4 contents were mimicked but not additive by alpha(1)-AR stimulation with phenylephrine and were abolished by an alpha(1B)-AR antagonist chloroethylclonidine and a PKC epsilon inhibitor PKC epsilon V1-2. These findings demonstrate that IHH exerts cardioprotection through attenuating excess ONOO- biosynthesis and TIMP-4 loss and sequential MMP-2 activation via the activation of alpha(1B)-AR/PKC epsilon pathway.

语种: 英语
所属项目编号: 2012CB518203 ; 2012ZX09501001 ; 81170119
项目资助者: Major State Basic Research Development Program of China ; National Science and Technology Major Project of China ; National Natural Science Foundation of China
WOS记录号: WOS:000337235300009
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/53422
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.Minist Educ, Key Lab Mol Cardiovasc Sci, Beijing, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Key Lab Stem Cell Biol, Shanghai, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Biol Sci, Inst Hlth Sci, Mol Cardiol Lab, Shanghai, Peoples R China
4.Peking Univ, Hosp 3, Inst Vasc Med, Beijing 100871, Peoples R China

Recommended Citation:
Gao, Ling,Chen, Le,Lu, Zhi-Zhen,et al. Activation of alpha(1B)-adrenoceptors contributes to intermittent hypobaric hypoxia-improved postischemic myocardial performance via inhibiting MMP-2 activation[J]. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY,2014,306(11):H1569-H1581.
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