Document Detail

Role of iNOS and peroxynitrite-matrix metalloproteinase-2 signaling in myocardial late preconditioning in rats.
MedLine Citation:
PMID:  20543091     Owner:  NLM     Status:  MEDLINE    
We have previously shown that the inhibition of myocardial nitric oxide (NO) and peroxynitrite-matrix metalloproteinase (MMP) signaling by early preconditioning (PC) is involved in its cardioprotective effect. Therefore, in the present study, we investigated the role of NO and peroxynitrite-MMP signaling in the development of late PC. PC was performed by five consecutive cycles of 4-min coronary occlusion and 4-min reperfusion in anesthetized rats in vivo. Twenty-four hours later, hearts were subjected to a 30-min coronary occlusion followed by 180-min reperfusion to measure infarct size. In separate experiments, heart tissue was sampled to measure biochemical parameters before and 3, 6, 12, or 24 h after the PC protocol, respectively. Late PC decreased infarct size, increased cardiac inducible NO synthase (iNOS) activity and gene expression, and decreased SOD activity at 24 h significantly compared with sham-operated controls. Late PC increased cardiac superoxide levels significantly at 24 h; however, it did not change cardiac NO levels. Cardiac peroxynitrite levels were significantly decreased. Downstream cellular targets of peroxynitrite, MMP-2 and MMP-9 activities were decreased in the late PC group at 24 h compared with the sham-operated group. To verify if PC-induced inhibition of MMPs had a causative role in the reduction of infarct size, in separate experiments, we measured infarct size after the pharmacological inhibition of MMPs by ilomastat and found a significant reduction of infarct size compared with the vehicle-treated group. In conclusion, this is the first demonstration that the inhibition of cardiac peroxynitrite-MMP signaling contributes to cardioprotection by late PC and that pharmacological inhibition of MMPs is able to reduce infarct size in vivo. Furthermore, increased expression of iNOS may play a role in the development of late PC; however, increased iNOS activity does not lead to increased NO production in late PC.
Péter Bencsik; Krisztina Kupai; Zoltán Giricz; Anikó Görbe; Judit Pipis; Zsolt Murlasits; Gabriella F Kocsis; Zoltán Varga-Orvos; László G Puskás; Csaba Csonka; Tamás Csont; Péter Ferdinandy
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-06-11
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  299     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-07-30     Completed Date:  2010-08-30     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H512-8     Citation Subset:  IM    
Cardiovascular Research Group, Dept. of Biochemistry, Univ. of Szeged, Dóm tér 9, Szeged H-6720, Hungary.
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MeSH Terms
Disease Models, Animal
Enzyme Activation
Indoles / pharmacology
Ischemic Preconditioning, Myocardial / methods*
Matrix Metalloproteinase 2 / antagonists & inhibitors,  metabolism*
Matrix Metalloproteinase 9 / metabolism
Myocardial Infarction / enzymology,  pathology,  prevention & control*
Myocardial Reperfusion Injury / enzymology,  pathology,  prevention & control*
Myocardium / enzymology*,  pathology
Nitric Oxide / metabolism
Nitric Oxide Synthase Type II / genetics,  metabolism*
Peroxynitrous Acid / metabolism*
Protease Inhibitors / pharmacology
Rats, Wistar
Signal Transduction* / drug effects
Superoxide Dismutase / metabolism
Superoxides / metabolism
Time Factors
Reg. No./Substance:
0/Indoles; 0/Protease Inhibitors; 10102-43-9/Nitric Oxide; 11062-77-4/Superoxides; 142880-36-2/ilomastat; 14691-52-2/Peroxynitrous Acid; EC Oxide Synthase Type II; EC protein, rat; EC Dismutase; EC Metalloproteinase 2; EC protein, rat; EC Metalloproteinase 9

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