| p38 mitogen-activated protein kinase inhibition improves cardiac function and attenuates left ventricular remodeling following myocardial infarction in the rat. | |
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MedLine Citation:
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PMID: 15489104 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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OBJECTIVES: The aim of this study was to examine the effect of the p38 mitogen-activated protein kinase (MAPK) inhibitor, RWJ-67657 (RWJ), on left ventricular (LV) dysfunction and remodeling post-myocardial infarction (MI) in rats. BACKGROUND: p38 MAPK signaling has been implicated in the progression of chronic heart failure. METHODS: From day 7 post-MI (coronary artery ligation), rats received either RWJ (50 mg/day, by gavage, n = 8, MI+RWJ) or vehicle (by gavage, n = 8, MI+V) for 21 days. Echocardiography was performed on day 6, before the commencement of treatment, and on day 27. In vivo hemodynamic measurements were made on day 28. Sham-operated rats served as controls. RESULTS: The LV end-diastolic pressure and lung/body weight ratio were reduced, whereas the maximum rate of rise of LV pressure was increased towards sham levels in MI+RWJ compared with MI+V. Baseline echocardiographic studies demonstrated uniform LV remodeling and dysfunction in MI rats. Fractional shortening (FS) further deteriorated in MI+V, whereas FS was preserved in MI+RWJ. Progressive LV dilation and infarct expansion observed in MI+V were inhibited in MI+RWJ. MI+RWJ also demonstrated increased myocyte hypertrophy in the peri-infarct and non-infarct zones, and reduced myocardial collagen and alpha-smooth muscle actin (SMA) immunoreactivity compared with MI+V. The antifibrotic effects of RWJ in vivo may reflect direct effects on cardiac fibroblasts, because RWJ attenuated transforming growth factor beta-1-stimulated collagen synthesis and alpha-SMA expression in isolated cardiac fibroblasts. RWJ also protected cultured myocytes from hydrogen peroxide-induced apoptosis. CONCLUSIONS: RWJ-67657 treatment post-MI had beneficial effects on LV remodeling and dysfunction, supporting a key role for p38 MAPK in pathologic cell signaling in these processes and its inhibition as a novel therapy. |
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Authors:
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Fiona See; Walter Thomas; Kerrie Way; Alex Tzanidis; Andrew Kompa; Dion Lewis; Silviu Itescu; Henry Krum |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of the American College of Cardiology Volume: 44 ISSN: 0735-1097 ISO Abbreviation: J. Am. Coll. Cardiol. Publication Date: 2004 Oct |
Date Detail:
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Created Date: 2004-10-18 Completed Date: 2004-11-30 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 8301365 Medline TA: J Am Coll Cardiol Country: United States |
Other Details:
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Languages: eng Pagination: 1679-89 Citation Subset: AIM; IM |
Affiliation:
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National Health and Medical Research Council Center of Clinical Research Excellence in Therapeutics, Department of Medicine, Monash University, Alfred Hospital, Commercial Road, Prahran, Victoria 3181, Australia. |
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis / drug effects, physiology Cells, Cultured Collagen Type I / metabolism Collagen Type II / metabolism Echocardiography Enzyme Inhibitors / pharmacology* Female Hemodynamics / drug effects, physiology Imidazoles / pharmacology* Immunoenzyme Techniques Myocardial Contraction / drug effects, physiology Myocardial Infarction / pathology, physiopathology* Myocardium / pathology Myocytes, Cardiac / drug effects, pathology, physiology Pyridines / pharmacology* Rats Rats, Sprague-Dawley Signal Transduction / drug effects, physiology Ventricular Dysfunction, Left / pathology, physiopathology Ventricular Remodeling / drug effects*, physiology p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*, physiology |
| Chemical | |
Reg. No./Substance:
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0/Collagen Type I; 0/Collagen Type II; 0/Enzyme Inhibitors; 0/Imidazoles; 0/Pyridines; 0/RWJ 67657; EC 2.7.11.24/p38 Mitogen-Activated Protein Kinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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