Fatty acid oxidation inhibition with PPARα activation (FOXIB/PPARα) for normalizing gene expression in heart failure?

Abstract

See also article by Lionetti et al. [7] (pages 454–461) in this issue. In the majority of patients with heart failure, the left ventricle is overloaded and cardiac hypertrophy occurs, which is associated with a dysregulated gene expression. A hallmark of hypertrophied animal hearts is the fetal phenotype, which has been characterized on the basis of a reduced or inadequate expression of α-myosin heavy chain (α-MHC) and the Ca2+ pump (SERCA2) of the sarcoplasmic reticulum (SR) that appears to be a marker of a great number of dysregulated genes [1] also involving Na+–Ca2+ exchange [2]. During progression of heart failure involving neuroendocrine activation, reprogramming of an even larger group of genes ensues. Microarray data has revealed at least 251 genes that are up- or downregulated upon heart failure [3]. The finding that many of the differentially expressed genes code for enzymes involved in energy metabolism might not be unexpected, since they are also reduced in the fetal period. Repression of genes that are responsible for the oxidation of fatty acids was particularly pronounced [1,4], which is indicative of reduced fatty acid utilization. Glucose oxidation is increased, which might nevertheless be inadequate when insulin resistance occurs [5]. Since PPARα was reduced as a consequence of pressure overload, the switch in fuel metabolism has been attributed to a reduced influence of PPARα [6]. Which of these many alterations represent initial events and are causative for the progression of heart failure? Which represent a compensatory reprogramming of gene expression? Until recently, it was still a matter of dispute whether the overloaded cardiomyocyte contributes to heart failure, and it was thought that deterioration of pump function arises primarily from an adverse remodeling of the extracellular matrix. This controversy can be settled by examining drugs that … *Corresponding author. Molecular Cardiology Laboratory, Department of Internal Medicine and Cardiology, Karl-von-Frisch-Strasse 1, 35033 Marburg, Germany. Tel.: +49 6421 286 5032; fax: +49 6421 286 8964. Email address: Rupp{at}staff.uni-marburg.de