Document Detail

Activation of α1B-adrenoceptors contributes to intermittent hypobaric hypoxia-improved post-ischemic myocardial performance via inhibiting MMP-2 activation.
MedLine Citation:
PMID:  24705558     Owner:  NLM     Status:  Publisher    
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 weeks) improved post-ischemic 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, α-actinin and troponin I. This protection was mimicked, but not augmented, by a MMP inhibitor doxycycline and lost by an α1-adrenoceptor (AR) antagonist prazosin. Furthermore, IHH increased myocardial α1A-AR and α1B-AR density but not α1D-AR after I/R. Concomitantly, IHH further enhanced the translocation of PKC epsilon (PKCε) and decreased the release of mitochondrial cytochrome c due to I/R via the activation of α1B-AR but not α1A-AR or α1D-AR. IHH-conferred cardioprotection in the post-ischemic contractile function, LDH release, MMP-2 activation, and nitrotyrosine as well as TIMP-4 contents were mimicked but not additive by α1-AR stimulation with phenylephrine and were abolished by an α1B-AR antagonist chloroethylclonidine and a PKCε inhibitor PKCε 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 α1B-AR/PKCε pathway.
Ling Gao; Le Chen; Zhi-Zhen Lu; Hong Gao; Lan Wu; Yi-Xiong Chen; Cai-Mei Zhang; Yu-Kun Jiang; Qing Jing; Youyi Zhang; Huang-Tian Yang
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-4-4
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  -     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2014 Apr 
Date Detail:
Created Date:  2014-4-7     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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