| Mineralocorticoid receptor inhibition ameliorates the transition to myocardial failure and decreases oxidative stress and inflammation in mice with chronic pressure overload. | |
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MedLine Citation:
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PMID: 15687129 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Although aldosterone, acting via mineralocorticoid receptors, causes left ventricular (LV) hypertrophy in experimental models of high-aldosterone hypertension, little is known about the role of aldosterone or mineralocorticoid receptors in mediating adverse remodeling in response to chronic pressure overload. METHODS AND RESULTS: We used the mineralocorticoid receptor-selective antagonist eplerenone (EPL) to test the role of mineralocorticoid receptors in mediating the transition from hypertrophy to failure in mice with chronic pressure overload caused by ascending aortic constriction (AAC). One week after AAC, mice were randomized to regular chow or chow containing EPL (200 mg/kg per day) for an additional 7 weeks. EPL had no significant effect on systolic blood pressure after AAC. Eight weeks after AAC, EPL treatment improved survival (94% versus 65%), attenuated the increases in LV end-diastolic (3.4+/-0.1 versus 3.7+/-0.1 mm) and end-systolic (2.0+/-0.1 versus 2.5+/-0.2 mm) dimensions, and ameliorated the decrease in fractional shortening (42+/-2% versus 34+/-4%). EPL also decreased myocardial fibrosis, myocyte apoptosis, and the ratio of matrix metalloproteinase-2/tissue inhibitor of matrix metalloproteinase-2. These beneficial effects of EPL were associated with less myocardial oxidative stress, as assessed by 3-nitrotyrosine staining, reduced expression of the adhesion molecule intercellular adhesion molecule-1, and reduced infiltration by macrophages. CONCLUSIONS: Mineralocorticoid receptors play an important role in mediating the transition from LV hypertrophy to failure with chronic pressure overload. The effects of mineralocorticoid receptor stimulation are associated with alterations in the interstitial matrix and myocyte apoptosis and may be mediated, at least in part, by oxidative stress and inflammation. |
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Authors:
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Gabriela M Kuster; Eugene Kotlyar; Mary K Rude; Deborah A Siwik; Ronglih Liao; Wilson S Colucci; Flora Sam |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: Circulation Volume: 111 ISSN: 1524-4539 ISO Abbreviation: Circulation Publication Date: 2005 Feb |
Date Detail:
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Created Date: 2005-02-02 Completed Date: 2005-07-11 Revised Date: 2007-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0147763 Medline TA: Circulation Country: United States |
Other Details:
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Languages: eng Pagination: 420-7 Citation Subset: AIM; IM |
Affiliation:
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Cardiovascular Medicine Section, Boston University Medical Center, Boston, Mass, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Aorta Apoptosis Blood Pressure Cell Size Chronic Disease Constriction, Pathologic / complications Drug Evaluation, Preclinical Fibrosis Heart Failure / etiology, prevention & control* Hypertrophy, Left Ventricular / complications*, drug therapy, physiopathology Intercellular Adhesion Molecule-1 / analysis Ligation Male Matrix Metalloproteinases / analysis Mice Myocarditis / drug therapy, etiology Myocardium / chemistry, pathology Myocytes, Cardiac / pathology Oxidative Stress / drug effects Pressure Random Allocation Receptors, Mineralocorticoid / antagonists & inhibitors*, physiology Spironolactone / analogs & derivatives*, pharmacology, therapeutic use* Tissue Inhibitor of Metalloproteinase-1 / analysis Tissue Inhibitor of Metalloproteinase-2 / analysis Tyrosine / analogs & derivatives*, analysis |
| Grant Support | |
ID/Acronym/Agency:
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HL20612/HL/NHLBI NIH HHS; HL61639/HL/NHLBI NIH HHS; K23 HL04423/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Receptors, Mineralocorticoid; 0/Tissue Inhibitor of Metalloproteinase-1; 0/eplerenone; 126547-89-5/Intercellular Adhesion Molecule-1; 127497-59-0/Tissue Inhibitor of Metalloproteinase-2; 3604-79-3/3-nitrotyrosine; 52-01-7/Spironolactone; 55520-40-6/Tyrosine; EC 3.4.24.-/Matrix Metalloproteinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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