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Cardiovascular Research Advance Access originally published online on January 10, 2008
Cardiovascular Research 2008 78(1):79-89; doi:10.1093/cvr/cvn001
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Cardiac hypertrophy is enhanced in PPAR{alpha}–/– mice in response to chronic pressure overload

Pascal J.H. Smeets1, Birgit E.J. Teunissen1, Peter H.M. Willemsen1, Frans A. van Nieuwenhoven1, Agnieszka E. Brouns2, Ben J.A. Janssen2, Jack P.M. Cleutjens3, Bart Staels4,5,6, Ger J. van der Vusse1 and Marc van Bilsen1,*

1 Department of Physiology, Cardiovascular Research Institute Maastricht, Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands
2 Department of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht, Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands
3 Department of Pathology, Cardiovascular Research Institute Maastricht, Maastricht University, PO Box 616, 6200 MD Maastricht, the Netherlands
4 Unité 545, INSERM, Lille F-59019, France
5 Department of Atherosclerose, Institute Pasteur de Lille, Lille F-59019, France
6 Faculté de Pharmacie, Université de Lille II, Lille F-59019, France

* Corresponding author. Tel: +31 433881204; fax: +31 433884166. E-mail address: marc.vanbilsen{at}fys.unimaas.nl

Aims: Peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}) is a nuclear receptor regulating cardiac metabolism that also has anti-inflammatory properties. Since the activation of inflammatory signalling pathways is considered to be important in cardiac hypertrophy and fibrosis, it is anticipated that PPAR{alpha} modulates cardiac remodelling. Accordingly, in this study the hypothesis was tested that the absence of PPAR{alpha} aggravates the cardiac hypertrophic response to pressure overload.

Methods and results: Male PPAR{alpha}–/– and wild-type mice were subjected to transverse aortic constriction (TAC) for 28 days. TAC resulted in a more pronounced increase in ventricular weight and left ventricular (LV) wall thickness in PPAR{alpha}–/– than in wild-type mice. Compared with sham-operated mice, TAC did not affect cardiac function in wild-type mice, but significantly depressed LV ejection fraction and LV contractility in PPAR{alpha}–/– mice. Moreover, after TAC mRNA levels of hypertrophic (atrial natriuretic factor, {alpha}-skeletal actin), fibrotic (collagen 1, matrix metalloproteinase-2), and inflammatory (interleukin-6, tumour necrosis factor-{alpha}, cyclo-oxygenase-2) marker genes were higher in PPAR{alpha}–/– than in wild-type mice. The mRNA levels of genes involved in fatty acid metabolism (long-chain acyl-CoA synthetase, hydroxyacyl-CoA dehydrogenase) were decreased in PPAR{alpha}–/– mice, but were not further compromised by TAC.

Conclusion: The present findings show that the absence of PPAR{alpha} results in a more pronounced hypertrophic growth response and cardiac dysfunction that are associated with an enhanced expression of markers of inflammation and extracellular matrix remodelling. These findings indicate that PPAR{alpha} exerts salutary effects during cardiac hypertrophy.

KEYWORDS PPAR{alpha}; Pressure-overload; Hypertrophy; Metabolism; Fibrosis; Inflammation

Time for primary review: 37 days


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