| Hyperlipidaemia induced by a high-cholesterol diet leads to the deterioration of guanosine-3',5'-cyclic monophosphate/protein kinase G-dependent cardioprotection in rats. | |
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MedLine Citation:
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PMID: 19845676 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND AND PURPOSE: Hyperlipidaemia interferes with cardioprotective mechanisms, but the cause of this phenomenon is largely unknown, although hyperlipidaemia impairs the cardioprotective NO-cGMP system. However, it is not known if natriuretic peptide-cGMP-protein kinase G (PKG) signalling is affected by hyperlipidaemia. Therefore, we investigated the cardioprotective efficacy of cGMP-elevating agents in hearts from normal and hyperlipidaemic rats. EXPERIMENTAL APPROACH: Male Wistar rats were rendered hyperlipidaemic by feeding with 2% cholesterol-enriched chow for 12 weeks. Hearts isolated from normal and hyperlipidaemic rats were perfused (Langendorff mode) and subjected to 30 min occlusion of the left main coronary artery, followed by 120 min reperfusion. 8-Br-cGMP (CG, 10 nM), B-type natriuretic peptide-32 (BNP, 10 nM), S-nitroso-N-acetyl-penicillamine (SNAP, 1 microM) were perfused from 10 min prior to coronary occlusion until the 15th min of reperfusion. Infarct size (% of ischaemic risk zone) was determined by triphenyltetrazolium staining. KEY RESULTS: Treatment with CG, SNAP or BNP decreased infarct size significantly in normal hearts from its control value of 41.6 +/- 2.9% to 15.5 +/- 2.4%, 23.3 +/- 3.0% and 25.3 +/- 4.6%, respectively (P < 0.05). Protection by BNP was abolished by co-perfusion of PKG inhibitors KT5823 (600 nM) or Rp-8pCPT-PET-cGMPs (1 microM), confirming its PKG dependence. In hearts from hyperlipidaemic rats, CG, SNAP or BNP failed to decrease infarct size. Hyperlipidaemia did not alter basal myocardial PKG content, but decreased its activity as assessed by phosphorylation of cardiac troponin I. CONCLUSIONS AND IMPLICATIONS: This is the first demonstration that defects in the cardioprotective cGMP-PKG system could be a critical biochemical anomaly in hyperlipidaemia. |
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Authors:
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Z Giricz; A Görbe; J Pipis; D S Burley; P Ferdinandy; G F Baxter |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-10-20 |
Journal Detail:
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Title: British journal of pharmacology Volume: 158 ISSN: 1476-5381 ISO Abbreviation: Br. J. Pharmacol. Publication Date: 2009 Nov |
Date Detail:
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Created Date: 2009-11-12 Completed Date: 2010-02-25 Revised Date: 2013-05-31 |
Medline Journal Info:
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Nlm Unique ID: 7502536 Medline TA: Br J Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 1495-502 Citation Subset: IM |
Affiliation:
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Department of Biochemistry, University of Szeged, Hungary. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Cardiotonic Agents / pharmacology* Cyclic GMP / analogs & derivatives, metabolism*, pharmacology Cyclic GMP-Dependent Protein Kinases / metabolism* Dietary Fats / toxicity Disease Models, Animal Hyperlipidemias / complications*, physiopathology Male Myocardial Infarction / etiology, prevention & control Myocardial Reperfusion Injury / physiopathology, prevention & control Natriuretic Peptide, Brain / pharmacology Phosphorylation Rats Rats, Wistar S-Nitroso-N-Acetylpenicillamine / pharmacology Troponin I / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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GR074567MA//Wellcome Trust |
| Chemical | |
Reg. No./Substance:
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0/Cardiotonic Agents; 0/Dietary Fats; 0/Troponin I; 114471-18-0/Natriuretic Peptide, Brain; 31356-94-2/8-bromocyclic GMP; 7665-99-8/Cyclic GMP; 79032-48-7/S-Nitroso-N-Acetylpenicillamine; EC 2.7.11.12/Cyclic GMP-Dependent Protein Kinases |
| Comments/Corrections | |
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