Aim: To investigate the efficacy of the peroxisome proliferator-activated
receptor-α (PPARα) 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 PPARγ 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.
Conclusion: The PPARα 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.
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