The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist, AVE8134, attenuates the progression of heart failure and increases survival in rats.
OBJECTIVE
To investigate the efficacy of the peroxisome proliferator-activated receptor-alpha (PPARalpha) agonist, AVE8134, in cellular and experimental models of cardiac dysfunction and heart failure.


METHODS
In Sprague Dawley rats with permanent ligation of the left coronary artery (post-MI), AVE8134 was compared to the PPARgamma agonist rosiglitazone and in a second study to the ACE inhibitor ramipril. In DOCA-salt sensitive rats, efficacy of AVE8134 on cardiac hypertrophy and fibrosis was investigated. Finally, AVE8134 was administered to old spontaneously hypertensive rats (SHR) at a non-blood pressure lowering dose with survival as endpoint. In cellular models, we studied AVE8134 on hypertrophy in rat cardiomyocytes, nitric oxide signaling in human endothelial cells (HUVEC) and LDL-uptake in human MonoMac-6 cells.


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.


CONCLUSIONS
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.
Linz
Wolfgang
W
Therapeutic Department Cardiovascular Diseases, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany.
Wohlfart
Paulus
P
Baader
Manuel
M
Breitschopf
Kristin
K
Falk
Eugen
E
Schäfer
Hans-Ludwig
HL
Gerl
Martin
M
Kramer
Werner
W
Rütten
Hartmut
H
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D001565:Benzoates / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D002316:Cardiotonic Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D002460:Cell Line; D018450:Disease Progression; D006333:Heart Failure / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D008297:Male; D015394:Molecular Structure; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010080:Oxazoles / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D047493:PPAR alpha / Q000819:agonists* / Q000378:metabolism; D017257:Ramipril / Q000627:therapeutic use; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D000077154:Rosiglitazone; D015996:Survival Rate; D045162:Thiazolidinediones / Q000627:therapeutic use
C545089:2-methyl-6-(3-(2-phenyloxazol-4-ylmethoxy)propoxymethyl)benzoic acid; D000806:Angiotensin-Converting Enzyme Inhibitors; D001565:Benzoates; D015415:Biomarkers; D002316:Cardiotonic Agents; D007004:Hypoglycemic Agents; D010080:Oxazoles; D047493:PPAR alpha; D045162:Thiazolidinediones; D000077154:Rosiglitazone; D052250:Nitric Oxide Synthase Type III; D017257:Ramipril