| Cardioprotection of bradykinin at reperfusion involves transactivation of the epidermal growth factor receptor via matrix metalloproteinase-8. | |
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MedLine Citation:
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PMID: 19583703 Owner: NLM Status: In-Process |
Abstract/OtherAbstract:
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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. |
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Authors:
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C Methner; U Donat; S B Felix; T Krieg |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-07-06 |
Journal Detail:
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Title: Acta physiologica (Oxford, England) Volume: 197 ISSN: 1748-1716 ISO Abbreviation: Acta Physiol (Oxf) Publication Date: 2009 Dec |
Date Detail:
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Created Date: 2009-10-30 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101262545 Medline TA: Acta Physiol (Oxf) Country: England |
Other Details:
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Languages: eng Pagination: 265-71 Citation Subset: IM |
Affiliation:
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Department of Cardiology, Ernst-Moritz-Arndt University, Greifswald, Germany. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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