Peroxisome proliferator-activated receptor ?/?: a new antihypertrophic drug target?

See article by Planavila et al.[6](pages 832–841) in this issue. In the normal adult heart, plasticity of ATP production is provided by coordinated changes in the expression of genes involved in cellular fatty acid (FA) utilization and glucose oxidation. The phenotypes of acquired forms of heart failure in human and animal models are associated with energy substrate changes accompanying a reduced mitochondrial FA oxidative capacity and a shift to glucose metabolism, resembling the fetal metabolic program [1]. High glucose conditions, initially serving as a protective response to support contractile function, stimulate the production of angiotensin II (Ang II), a known pathological modulator of cardiac remodeling [2]. Peroxisome proliferator-activated receptors (PPARs) are gene regulatory systems that regulate the transcription of an array of genes involved in cellular fatty acid utilization pathways. PPARs are ligand-dependent transcription factors belonging to the nuclear receptor superfamily. They are designed to rapidly respond to fluctuating substrate and metabolic intermediates. They regulate pathways involved in FA utilization upstream to the transcriptional regulatory network including nuclear respiratory factors 1 and 2 and mitochondrial transcription factor A [3]. PPARs have 3 isoforms, α, β/δ, and γ, that regulate lipid and glucose metabolism, participate in the regulation of cell growth and migration and in the control of oxidative stress and inflammation in the cardiovascular system [4,5]. Functional specificity among the PPARs is achieved by isoform-specific tissue distribution, ligands, and cofactor interaction. As shown by the paper by Planavila et al. [6] in this issue of Cardiovascular Research, there is a certain degree of functional overlap between PPARα and β/δ in inhibition of cellular transduction pathways leading to cardiac hypertrophic remodeling. In addition to conventional pharmacotherapy (angiotensin-converting enzyme inhibitors, β-adrenoreceptor blockers), selective PPARα and γ activators, partial agonists, or dual α/γ activators may lead to interesting antihypertrophic cardiovascular therapies. However, potential applications of targeting these negative regulators, including PPARβ/δ, for complex therapies require vigorous verification of their role in adaptive and maladaptive remodeling and limitations in the prevention and treatment of left ventricular hypertrophy and heart failure. PPARα–PPARα is a primary transcriptional regulator of fat metabolism in tissues with high FA oxidation rates such as heart, liver, kidney, and skeletal muscle. It regulates every step of cardiac FA utilization through the induction of target genes involved in fatty acid metabolism. Mice deficient in PPARα have a reduced capacity for constitutive myocardial β-oxidation of medium and long chain fatty acids and a prolonged response to inflammatory stimuli and age-dependent myocardial fibrosis (for review see [3]). Deactivation of the PPARα signaling pathway by MAP kinases, which are rapidly activated by diverse prohypertrophic mitogenic stimuli, is an early step in the downregulation of fatty acid oxidation (FAO) in the hypertrophied heart [7]. PPARα ligands have been shown to reduce cardiac hypertrophy and inflammation by interfering with the nuclear factor (NF)-κB transactivation capacity through a direct protein–protein interaction with the p65 subunit [8]. Antihypertrophic activity of PPARα activation interrupts other signaling events promoted by the hypertrophic inducer endothelin (ET) such as c-Jun N-terminal protein kinase activation, c-Jun phosphorylation, and c-Jun induction in cardiomyocytes. The PPARα ligand, fenofibrate, inhibits ET-1 promoter activity, prepro-ET-1 mRNA expression, and hypertrophy in ET-1-stimulated cardiomyocytes [9]. PPARγ–Although PPARγ is expressed in the heart at levels much below that of PPARα and PPARβ/δ, recent results suggest that the PPARγ-dependent pathway is involved in the hypertrophic response and inhibits the development of cardiac hypertrophy, counteracting diverse prohypertrophic signaling pathways. PPARγ may suppress the development of cardiac hypertrophy by antagonizing the activities of transcription factors such as AP-1, STAT3, and GATA4 [10, 11]. The thiazolidinediones, high-affinity ligands for PPARγ, inhibit Ang-II-induced cardiac hypertrophy in vitro and pressure overload-induced cardiac hypertrophy in vivo. Pressure overload induces more marked cardiac hypertrophy in heterozygous PPARγ-deficient mice than in wild-type mice [10]. However, the use of thiazolidinediones may be limited to patients with less advanced cardiovascular disease because PPARγ activators may trigger aggravation of heart failure as a consequence of their insulinomimetic action. PPARβ/δ–The role of PPARβ/δ in the regulation of cardiac metabolism and signaling to downstream prohypertrophic pathways has been relatively unexplored (for review see [12]). CRE-lox-mediated, cardiomyocyte-restricted deletion of PPARβ/δ in mice downregulates constitutive expression of key FAO genes and decreases basal myocardial FAO. PPARβ/δ-deficient mice display cardiac dysfunction, progressive myocardial lipid accumulation, cardiac hypertrophy, and congestive heart failure [13]. The study by Planavila et al. [6] highlights the regulatory role of PPARδ as an emerging player in the loss of substrate utilization flexibility in hypertrophied and failing heart. Treatment with the PPARβ/δ agonist L-165041 prevented the reduction in the transcript level of genes involved in lipid metabolism including muscle-type carnitine palmytoyltransferase determining the flux of mitochondrial β-oxidation and pyruvate dehydrogenase kinase 4 (PDK-4). PDK-4 is a suppressor of glucose oxidation via its inhibitory effect on the pyruvate dehydrogenase complex. The work of Planavila et al. [6] provides evidence that PPARβ/δ and PPARα regulate overlapping sets of genes or superimposed pathways involved in cardiac hypertrophic remodeling. PPARβδ is unlikely to compensate for PPARα in all physiological reactions but represents a new negative regulator of cardiac hypertrophic remodeling that acts similar to PPARα via suppression of the NF-κB prohypertrophic pathway. Planavila et al. [6] have demonstrated that L 165041, the selective PPARβ/δ activator, decreases LPS-stimulated NF-κB binding activity in H9c2 myotubes and enhances physical interaction between PPARβ/δ and the p65 subunit of NF-κB. The findings by Planavila et al. [6] provide a new insight into several regulatory steps in response to growth signals and into the role of PPARβ/δ in this signaling network. It would be of interest to correlate changes in cardiac energetics caused by PPAR activation with suppression of the genes involved in glucose transport and utilization, which induces a diabetic state and secondarily may cause left ventricular hypertrophy similar to PPARγ agonists [14]. The identification of prohypertrophic stimuli leading to reduction in PPARβ/δ expression and hemodynamic characterization in long-term animal models are necessary to delineate therapeutic strategies specifically targeting PPARβ/δ in the treatment of cardiac hypertrophy and failure.