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Cardioprotection of bradykinin at reperfusion involves transactivation of the epidermal growth factor receptor via matrix metalloproteinase-8.
MedLine Citation:
PMID:  19583703     Owner:  NLM     Status:  In-Process    
AIM: The endogenous autacoid bradykinin (BK) reportedly reduces myocardial infarct size when given exogenously at reperfusion. Muscarinic and opioid G-protein-coupled receptors are equally protective and have been shown to couple through a matrix metalloproteinase (MMP)-dependent transactivation of the epidermal growth factor receptor (EGFR). Here we test whether BK protects the rat heart through the EGFR by an MMP-dependent pathway. METHODS: Infarct size was measured in isolated perfused rat hearts undergoing 30 min regional ischaemia followed by 120 min reperfusion. In additional studies HL-1 cardiomyocytes were loaded with tetramethylrhodamine ethyl to measure their mitochondrial membrane potential (Psim). Adding the calcium ionophore calcimycin, causes Psim-collapse presumably due to calcium-induced mitochondrial permeability transition. RESULTS: As expected, BK (100 nmol L(-1)) started 5 min prior to reperfusion reduced infarct size from 38.9 +/- 2.0% of the ischaemic zone in control hearts to 22.2 +/- 3.3% (P < 0.001). Co-infusing the EGFR inhibitor AG1478, the broad-spectrum MMP-inhibitor GM6001, or a highly selective MMP-8 inhibitor abolished BK's protection, thus suggesting an MMP-8-dependent EGFR transactivation in the signalling. Eighty minutes of exposure to calcimycin reduced the mean cell fluorescence to 37.4 +/- 1.8% of untreated cells while BK could partly preserve the fluorescence and, hence, protect the cells (50.5 +/- 2.3%, P < 0.001). The BK-induced mitochondrial protection could again be blocked by AG1478, GM6001 and MMP-8 inhibitor. Finally, Western blotting revealed that BK's protection was correlated with increased phosphorylation of EGFR and its downstream target Akt. CONCLUSION: These results indicate that BK at reperfusion triggers its protective signalling pathway through MMP-8-dependent transactivation of the EGFR.
C Methner; U Donat; S B Felix; T Krieg
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-07-06
Journal Detail:
Title:  Acta physiologica (Oxford, England)     Volume:  197     ISSN:  1748-1716     ISO Abbreviation:  Acta Physiol (Oxf)     Publication Date:  2009 Dec 
Date Detail:
Created Date:  2009-10-30     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101262545     Medline TA:  Acta Physiol (Oxf)     Country:  England    
Other Details:
Languages:  eng     Pagination:  265-71     Citation Subset:  IM    
Department of Cardiology, Ernst-Moritz-Arndt University, Greifswald, Germany.
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