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Cardiovascular Research Advance Access first published online on April 25, 2008
This version [Corrected Proof] published online on May 17, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn106
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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

Overexpression of human truncated peroxisome proliferator-activated receptor {alpha} induces apoptosis in HL-1 cardiomyocytes

Javier Beaumont1, Teresa Arias1, Susana Ravassa1 and Javier Díez1,2,*

1 Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, CIMA, Avda. Pío XII 55, 31008 Pamplona, Spain
2 Department of Cardiology and Cardiovascular Surgery, University Clinic, School of Medicine, University of Navarra, Pamplona, Spain

* Corresponding author. Tel: +34 948 194700 (ext. 3000); fax: +34 948 194716. E-mail address: jadimar{at}unav.es

Aims: Our goal was to analyse whether truncated peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) overexpression induces apoptosis of cardiomyocytes.

Methods and results: We constructed a recombinant vector of human truncated PPAR{alpha} and a mammalian expression vector to transfect PPAR{alpha} into a line of murine cardiomyocytes designated HL-1. Four hallmarks of apoptosis were measured in these transfected cells: depolarization of mitochondrial membrane, activation of caspase-3, phosphatidylserine (PS) externalization, and DNA fragmentation. Co-transfection with human cyclic adenosine monophosphate response element-binding protein (CREB) and human CREB binding protein (CBP) and analysis of apoptosis regulatory proteins, Bcl-2 and Bax, were also performed in truncated PPAR{alpha}-transfected cells to determine the potential mechanisms by which truncated PPAR{alpha} may influence apoptosis. Progressive depolarization of mitochondrial membrane, activation of caspase-3, PS externalization, DNA fragmentation, and cell death were observed in HL-1 cells upon increasing levels of transfected truncated PPAR{alpha}. The expression of the antiapoptotic protein Bcl-2 decreased in transfected HL-1 cardiomyocytes, whereas no changes in the proapoptotic protein Bax were observed in these cells. Overexpression of CREB plus CBP abolished the inhibitory effect of truncated PPAR{alpha} on Bcl-2 protein.

Conclusion: These results demonstrate that human truncated PPAR{alpha} overexpression induces apoptosis in HL-1 cardiomyocytes. In addition, our findings suggest that truncated PPAR{alpha} may induce cardiomyocyte apoptosis through the inhibition of the antiapoptotic protein, Bcl-2. It is proposed that competition with CREB for coactivators like CBP could be involved in this inhibitory effect.

KEYWORDS Truncated PPAR{alpha}; Apoptosis; Cardiomyocytes

Time for primary review: 30 days


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