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Abstract: Objective: To investigate whether cardiac expression of the nuclear peroxisome proliferator-activated receptor α (PPARα) is altered in patients with hypertensive heart disease (HHD). Methods: We studied endomyocardial septal biopsies from 24 patients with essential hypertension divided into three groups: 6 without left ventricular hypertrophy (LVH) (HT group), 10 with LVH (LVH group), and 8 with LVH and heart failure (HF) (HF group). The expression of two PPARα isoforms (the native active and the truncated inhibitory) was analyzed by Western blot and reverse transcription polymerase chain reaction (RT–PCR), and two PPARα target genes were evaluated by RT–PCR. Histomorphological features were evaluated in a second myocardial sample from LVH and HF groups. Results: Whereas the expression of native PPARα protein was lower (p <0.05) in LVH and HF groups than in the HT group, truncated PPARα protein was overexpressed (p <0.001) in the HF group as compared with LVH and HT groups. The mRNA expression of native and truncated PPARα was similar in the three groups of hypertensives. In addition, a progressive decrease (p for trend<0.05) in the two PPARα target genes mRNA expression was observed among HT, LVH and HF groups. The amount of truncated PPARα protein correlates directly with cardiomyocytes apoptosis and inversely with cardiomyocytes density in patients with HHD. In addition, the expression of truncated PPARα protein was directly correlated with left ventricular volumes, and inversely with ejection fraction in all hypertensives. Conclusions: These findings suggest that post-transcriptional regulation of PPARα isoforms is altered in patients with HHD, namely in those developing HF. An excess of the truncated inhibitory isoform may be involved in hypertensive left ventricular failure and remodeling. [Copyright &y& Elsevier]

Heart failure is a complex syndrome and is one of the main causes of morbidity and mortality in developed countries. Despite considerable research effort in recent years, heart failure prevention and treatment strategies still suffer significant limitations. New theoretical and technical approaches are, therefore, required. It is in this context that the "omic" sciences have a role to play in heart failure. The incorporation of "omic" methodologies into the study of human disease has substantially changed biological approaches to disease and has given an enormous impetus to the search for new disease mechanisms, as well as for novel biomarkers and therapeutic targets. The application of genomics, proteomics and metabonomics to heart failure research could increase our understanding of the origin and development of the different processes contributing to this syndrome, thereby enabling the establishment of specific diagnostic profiles and therapeutic templates that could help improve the poor prognosis associated with heart failure. This brief review contains a short description of the fundamental principles of the "omic" sciences and an evaluation of how these new techniques are currently contributing to research into human heart failure. The focus is mainly on the analysis of gene expression microarrays in the field of genomics and on studies using two-dimensional electrophoresis with mass spectrometry in the area of proteomics.

Aims: Our goal was to analyse whether truncated peroxisome proliferator-activated receptor alpha (PPARalpha) overexpression induces apoptosis of cardiomyocytes., Methods and Results: We constructed a recombinant vector of human truncated PPARalpha and a mammalian expression vector to transfect PPARalpha 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 PPARalpha-transfected cells to determine the potential mechanisms by which truncated PPARalpha 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 PPARalpha. 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 PPARalpha on Bcl-2 protein., Conclusion: These results demonstrate that human truncated PPARalpha overexpression induces apoptosis in HL-1 cardiomyocytes. In addition, our findings suggest that truncated PPARalpha 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.