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Cardiovascular Research Advance Access [Accepted Manuscript] published online on June 4, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp183
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

A potential link between PPAR signaling and the pathogenesis of arrhythmogenic right ventricular cardiomyopathy (ARVC)

Fatima Djouadi, PhD1, Yves Lecarpentier, MD-PhD2,3, Jean-Louis Hébert, MD-PhD2, Philippe Charron, MD-PhD4, Jean Bastin, PhD1 and Catherine Coirault, MD-PhD2,5

1 Université Paris Descartes, CNRS UPR9078, Faculté Necker, Assistance Publique-Hôpitaux de Paris, Paris
2 Services d'Explorations CardioRespiratoires, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre
3 Centre de Recherche Clinique, Hôpital de Meaux
4 Université Pierre et Marie Curie-Paris 6, Inserm U621 and Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris
5 INSERM U974, UPMC Univ Paris 06, Paris

Address for correspondence: Catherine Coirault, INSERM U974, GH Pitié-Salpétrière, 47 Bd de l'Hôpital, 75651 PARIS Cedex 13. Tel: 331 42 16 57 55, Fax: 331 42 16 57 00, E-mail: c.coirault{at}institut-myologie.org

Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by major fibro-fatty replacement of the right ventricle (RV). We hypothesized that changes in peroxisome proliferators-activated receptor (PPAR) signaling contributed to myocardium fatty accumulation and contractile dysfunction in ARVC.

Methods: Real-time quantitative RT-PCR and Western blotting were used to assess cardiac expression of PPAR{alpha} and {gamma} and two of their downstream target genes – medium-chain acyl-CoA dehydrogenase (MCAD) and phosphoenolpyruvate carboxykinase (PEPCK) – in both right and left ventricles (RV, LV) from 5 controls and 5 ARVC patients. In vitro motility assays were used to analyze functional properties of myosin.

Results: In the RV, sliding velocity was nearly twofold lower in ARVC than in controls, whereas a 10 % reduction in velocity values was noted between ARVC and non-failing myocardium in the LV. In controls, PPAR{alpha} and MCAD mRNA and protein levels were higher in the RV compared to the LV. In ARVC, the expression of PPAR{alpha} and MCAD mRNA and/or proteins was decreased in both RV and LV. RV from ARVC was also characterized by a dramatic activation of the PPAR{gamma} pathway, as attested by the increase in PPAR{gamma} mRNA and protein (+500% and +270%, respectively, each p<0.001) and by the induction of PEPCK gene. In contrast, the LV of ARVC heart exhibited no changes in the expression of the PPAR{gamma} regulatory pathway compared to control.

Conclusion: ARVC is associated with major disturbances in the PPAR{alpha} and PPAR{gamma} signaling pathway in the RV that may contribute to intracellular lipid overload and severe myosin dysfunction.

KEYWORDS cardiomyopathy; contractile apparatus; heart failure; lipid signaling

Time for primary review: 50 Days


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