| Effects of fenofibrate on cardiac remodeling in aldosterone-induced hypertension. | |
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MedLine Citation:
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PMID: 17606858 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Hypertension and cardiac remodeling are associated with myocardial fibrosis, left ventricular (LV) hypertrophy, and diastolic heart failure. Fenofibrate suppresses aldosterone-mediated increases in myocyte matrix metalloproteinase activity and extracellular signal-regulated kinase phosphorylation. It is unknown whether the peroxisome proliferator-activated receptor-alpha agonist, fenofibrate, improves cardiac remodeling in a model of aldosterone-induced hypertension and LV hypertrophy. Twelve-week-old uninephrectomized FVB mice received 1% NaCl drinking water. Miniosmotic pumps delivered saline or aldosterone for 4 weeks. Mice were either untreated (n=14) or treated with fenofibrate 100 mg/kg per day (n=12) for 1 week before and 4 weeks after surgery. Aldosterone increased systolic blood pressure in untreated mice versus saline-untreated mice (134+/-3 versus 91+/-3 mm Hg; P<0.01). This was unaffected by fenofibrate (131+/-3 mm Hg). Aldosterone increased LV end-diastolic and end-systolic dimensions, which were significantly attenuated by fenofibrate (3.8+/-0.1 versus 3.5+/-0.1 mm, and 1.5+/-0.1 versus 1.15+/-0.1 mm, respectively). Fenofibrate also decreased aldosterone-induced LV hypertrophy (LV weight/body weight, 4.1+/-0.2 versus 4.6+/-0.1 mg/g) and improved percent LV fractional shortening (67+/-7% versus 60+/-2%). Additionally, fenofibrate ameliorated the increased matrix metalloproteinase-2/tissue inhibitors of metalloproteinase-2 ratio and fibrosis seen in aldosterone-untreated hearts (P<0.05 for both). Furthermore, in aldosterone-untreated hearts, fenofibrate decreased transforming growth factor-beta, collagen type III (P<0.05 for both), and collagen type I (P<0.01) protein expression. Conversely fenofibrate increased peroxisome proliferator-activated receptor-alpha, peroxisome proliferator-activated receptor-gamma coactivator-1alpha expression, and acetyl coenzyme A carboxylase phosphorylation (P<0.05 for all) in aldosterone-infused hearts; uncoupling protein-3 and medium-chain acyl coenzyme A dehydrogenase protein expression decreased with fenofibrate (P<0.05 and P<0.01, respectively, versus aldosterone-infused), suggesting that improved myocardial remodeling is independent of fatty acid oxidation. Thus, fenofibrate improved aldosterone-induced LV hypertrophy independently of an effect on blood pressure with decreased fibrosis and altered extracellular matrix. |
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Authors:
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Nathan K Lebrasseur; Toni-Ann S Duhaney; Deepa S De Silva; Lei Cui; Peter C Ip; Lija Joseph; Flora Sam |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2007-07-02 |
Journal Detail:
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Title: Hypertension Volume: 50 ISSN: 1524-4563 ISO Abbreviation: Hypertension Publication Date: 2007 Sep |
Date Detail:
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Created Date: 2007-08-23 Completed Date: 2007-09-18 Revised Date: 2007-12-03 |
Medline Journal Info:
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Nlm Unique ID: 7906255 Medline TA: Hypertension Country: United States |
Other Details:
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Languages: eng Pagination: 489-96 Citation Subset: IM |
Affiliation:
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Muscle and Aging Research Unit, Boston University School of Medicine, MA 02118, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Aldosterone*
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pharmacology Animals Blood Pressure / drug effects Extracellular Matrix / metabolism Fibrosis Heart / drug effects, physiopathology Heart Rate / drug effects Hypertension / chemically induced*, pathology, physiopathology* Hypertrophy, Left Ventricular / pathology Lipid Metabolism / drug effects Matrix Metalloproteinase 2 / metabolism Mice Mice, Inbred Strains Myocardium / metabolism, pathology Peroxisome Proliferator-Activated Receptors / agonists Procetofen / pharmacology* Systole Tissue Inhibitor of Metalloproteinase-2 / metabolism Ventricular Remodeling / drug effects* |
| Grant Support | |
ID/Acronym/Agency:
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HL079099/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Peroxisome Proliferator-Activated Receptors; 127497-59-0/Tissue Inhibitor of Metalloproteinase-2; 49562-28-9/Procetofen; 52-39-1/Aldosterone; EC 3.4.24.24/Matrix Metalloproteinase 2 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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