Abstract | AIM: METHODS: RESULTS: In post-MI rats, AVE8134 dose-dependently improved cardiac output, myocardial contractility and relaxation and reduced lung and left ventricular weight and fibrosis. In contrast, rosiglitazone exacerbated cardiac dysfunction. Treatment at AVE8134 decreased plasma proBNP and arginine and increased plasma citrulline and urinary NOx/ creatinine ratio. In DOCA rats, AVE8134 prevented development of high blood pressure, myocardial hypertrophy and cardiac fibrosis, and ameliorated endothelial dysfunction. Compound treatment increased cardiac protein expression and phosphorylation of eNOS. In old SHR, treatment with a low dose of AVE8134 improved cardiac and vascular function and increased life expectancy without lowering blood pressure. AVE8134 reduced phenylephrine-induced hypertrophy in adult rat cardiomyocytes. In HUVEC, Ser-1177-eNOS phosphorylation but not eNOS expression was increased. In monocytes, AVE8134 increased the expression of CD36 and the macrophage scavenger receptor 1, resulting in enhanced uptake of oxidized LDL. CONCLUSION: The PPARalpha agonist AVE8134 prevents post-MI myocardial hypertrophy, fibrosis and cardiac dysfunction. AVE8134 has beneficial effects against hypertension-induced organ damages, resulting in decreased mortality. The compound exerts its protective properties by a direct effect on cardiomyocyte hypertrophy, but also indirectly via monocyte signaling and increased endothelial NO production.Acta Pharmacologica Sinica (2009) 30: 935-946; doi: 10.1038/aps.2009.58; published online 8 June 2009.
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Authors | Wolfgang Linz, Paulus Wohlfart, Manuel Baader, Kristin Breitschopf, Eugen Falk, Hans-Ludwig Schäfer, Martin Gerl, Werner Kramer, Hartmut Rütten |
Journal | Acta pharmacologica Sinica
(Acta Pharmacol Sin)
Vol. 30
Issue 7
Pg. 935-46
(Jul 2009)
ISSN: 1745-7254 [Electronic] United States |
PMID | 19503102
(Publication Type: Journal Article)
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Chemical References |
- 2-methyl-6-(3-(2-phenyloxazol-4-ylmethoxy)propoxymethyl)benzoic acid
- Angiotensin-Converting Enzyme Inhibitors
- Benzoates
- Biomarkers
- Cardiotonic Agents
- Hypoglycemic Agents
- Oxazoles
- PPAR alpha
- Thiazolidinediones
- Rosiglitazone
- Nitric Oxide Synthase Type III
- Ramipril
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Topics |
- Angiotensin-Converting Enzyme Inhibitors
(therapeutic use)
- Animals
- Benzoates
(chemistry, metabolism, therapeutic use)
- Biomarkers
(metabolism)
- Cardiotonic Agents
(chemistry, metabolism, therapeutic use)
- Cell Line
- Disease Progression
- Heart Failure
(drug therapy, pathology, physiopathology)
- Hemodynamics
- Humans
- Hypoglycemic Agents
(therapeutic use)
- Male
- Molecular Structure
- Nitric Oxide Synthase Type III
(metabolism)
- Oxazoles
(chemistry, metabolism, therapeutic use)
- PPAR alpha
(agonists, metabolism)
- Ramipril
(therapeutic use)
- Rats
- Rats, Inbred SHR
- Rats, Sprague-Dawley
- Rosiglitazone
- Survival Rate
- Thiazolidinediones
(therapeutic use)
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