Cardiovascular Research Advance Access originally published online on June 4, 2009
Cardiovascular Research 2009 84(1):83-90; doi:10.1093/cvr/cvp183
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
A potential link between peroxisome proliferator-activated receptor signalling and the pathogenesis of arrhythmogenic right ventricular cardiomyopathy
1 Université Paris Descartes, CNRS UPR9078, Faculté Necker, Assistance Publique-Hôpitaux de Paris, Paris, France
2 Service d'Explorations CardioRespiratoires, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin-Bicêtre, France
3 Centre de Recherche Clinique, Hôpital de Meaux, Meaux, France
4 Université Pierre et Marie Curie-Paris 6, Inserm U621 and Assistance Publique-Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Paris, France
5 INSERM U974, UPMC Univ Paris 06, GH Pitié-Salpétrière, 47 Bd de l'Hôpital, 75651 Paris Cedex 13, France
* Corresponding author. Tel: +33 1 42 16 57 55; fax: +33 1 42 16 57 00. E-mail address: 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 proliferator-activated receptor (PPAR) signalling contributed to myocardium fatty accumulation and contractile dysfunction in ARVC.
Methods and results: Real-time quantitative reverse transcriptase–polymerase chain reaction and western blotting were used to assess cardiac expression of PPAR
and 
and two of their downstream target genes—medium-chain acyl-CoA dehydrogenase (MCAD) and phosphoenolpyruvate carboxykinase (PEPCK)—in both RV and left ventricle (LV) from five controls and five ARVC patients. In vitro motility assays were used to analyse functional properties of myosin. In the RV, sliding velocity was nearly two-fold 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 and MCAD mRNA and protein levels were higher in the RV compared with the LV. In ARVC, the expression of PPAR 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 pathway, as attested by the increase in PPAR 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 regulatory pathway compared with control.
Conclusion: ARVC is associated with major disturbances in the PPAR and PPAR signalling pathway in the RV that may contribute to intracellular lipid overload and severe myosin dysfunction.
KEYWORDS Cardiomyopathy; Contractile apparatus; Heart failure; Lipid signalling
Time for primary review: 50 days