Role of the peroxisome proliferator-activated receptor alpha (PPARALFA) system in the pathophysiology of heart failure

Résumé

ROLE OF THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA (PPARα) SYSTEM IN THE PATHOPHYSIOLOGY OF HEART FAILURE Teresa Arias Guedón SCHOOL OF SCIENCES. UNIVERSITY OF NAVARRA (SPAIN). 2010 The development of HF involves complex interactions between genetic and environmental factors, leading to a number of myocardial alterations including increased cardiomyocyte apoptosis and impaired energetics. One of the factors involved in these alterations is the transcription factor PPARα. The L162V (rs1800206), Intron 7 G/C (rs4253778) and rs135551 are three polymorphisms of the human PPARα gene (PPARA) associated with different cardiovascular pathologies. Moreover, two different PPARα isoforms have been described in human myocardial tissue: a native isoform that regulates myocardial energy production, and a truncated isoform that might be associated with cardiomyocyte apoptosis. In the present study we have studied the role of the PPARα system in HF development, in two different directions: on one hand, we have analyzed the distribution of the rs1800206, rs4253778 and rs135551 polymorphisms of the PPARA gene in a HF population. Functional studies of the polymorphisms were also performed in HL-1 cardiomyocytes and myocardial human tissue. On the other hand, we have analyzed the pro-apoptotic effect of truncated PPARα overexpression in HL-1 cardiomyocytes. We have observed that the V162 allele of the rs1800206 polymorphism was more frequent in stage C patients than in stages A and B and control subjects. Patients with the V162 allele exhibited decreased myocardial expression of FAO-related PPARα target genes. Moreover cardiomyocytes transfected with the V162 allele presented decreased PPAR transcriptional activity and expression of a FAO-related PPARα target gene. We have also observed that truncated PPARα overexpression may induce cardiomyocyte apoptosis through the inhibition of the anti-apoptotic pathway CREB-Bcl-2. Thesis supervisor Thesis co-supervisor Javier Beaumont Ezcurra, PhD. Javier Díez Martínez, MD, PhD