Copyright © 2005, European Society of Cardiology
Fatty acid oxidation inhibition with PPAR
activation (FOXIB/PPAR) for normalizing gene expression in heart failure?
Molecular Cardiology Laboratory, Department of Internal Medicine and Cardiology, Philipps University of Marburg, Marburg, Germany
* 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
Received 23 March 2005; accepted 31 March 2005
See also article by Lionetti et al. [7] (pages 454–461) in this issue.
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1. Gene expression of overloaded cardiomyocytes |
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 Top 1. Gene expression of... 2. Oxfenicine treatment in...3. Etomoxir counteracts a...4. CPT I inhibition...References |
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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
-myosin heavy chain (-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 PPAR was reduced as a consequence of pressure overload, the switch in fuel metabolism has been attributed to a reduced influence of PPAR [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 interfere with the altered gene expression of cardiomyocytes and by assessing consequences for the progression of heart failure. In these experiments, the overload of the heart should not be reduced by the treatment. As an example, antihypertensive ACE inhibitor treatment of infarcted overloaded heart reduces the overload and defects in gene expression of cardiomyocytes, therefore, cannot be traced. Ideally, a given compound should not have acute inotropic or vasodilatory actions. As reported in this issue of Cardiovascular Research, Lionetti et al. [7] studied such a compound in a large animal model of severe heart failure. They addressed the question whether partial inhibition of fatty acid oxidation of the heart in a rapidly progressing model of heart failure due to rapid pacing accelerates or slows heart failure. Keeping in mind that fatty acids are the main fuel for the heart and that the failing heart might already be energy starved [5], the outcome is not straightforward. By blocking mitochondrial carnitine palmitoyltransferase I (CPT I) activity, the already reduced fatty acid utilization is impaired further and an even more prominent shift to glucose utilization is expected.
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2. Oxfenicine treatment in a dog model of ischemic heart failure |
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Top1. Gene expression of...2. Oxfenicine treatment in...3. Etomoxir counteracts a...4. CPT I inhibition...References |
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Lionetti et al. [7] provide clear evidence that the CPT I inhibitor oxfenicine slowed progression of heart failure and preserved pump function. The treatment delayed the onset of failure by approximately 1 week, reduced left ventricular remodeling and prevented various changes in protein phenotype. In particular, activation of matrix metalloproteinase (MMP)-2 and -9, which are known to be involved in cardiac dilatation, was prevented and end-diastolic diameter was reduced. Since the hearts still failed, it has to be concluded that activation of MMP-2 and -9 only partly contributes to cardiac dilatation, but certainly does not represent an epiphenomenon. The beneficial effects can most probably not be attributed to putatively antioxidative properties of oxfenicine. Another CPT I inhibitor, etomoxir, also retarded dilatation of the pressure-overloaded heart [8], and this compound is not expected to exhibit antioxidative effects. Since the reduction in the mRNA levels of the genes PPAR
, RXR, GAPDH, citrate synthase, m-CPT I, PDK-4 and UCP3 of untreated dogs with heart failure were prevented by oxfenicine, the question emerges whether these genes belong to the group of causative genes for heart failure progression or represent a compensatory reprogramming due to the impaired heart function. At first glance, the findings on oxfenicine might be puzzling. Mechanisms underlying the improvement in heart function become apparent when comparing oxfenicine with etomoxir. Although oxfenicine differs in the chemical structure (L-hydroxyphenylglycine) from etomoxir (2-[6-(4-chlorophenoxy)hexyl]oxirane-2-carboxylate), both have been developed as CPT I inhibitors and appear to have a similar action in overloaded and failing heart. |
3. Etomoxir counteracts a dysregulated gene expression of overloaded cardiomyocytes |
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Top1. Gene expression of...2. Oxfenicine treatment in...3. Etomoxir counteracts a...4. CPT I inhibition...References |
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Etomoxir has been developed as a hypoglycemic and hypolipidemic compound. In contrast to the physiological inhibitor malonyl-CoA, etomoxir inhibits irreversibly a certain proportion of CPT I molecules and thereby reduces the mitochondrial uptake and oxidation of fatty acids (Fig. 1). CPT I inhibition alone, however, would reduce an already diminished fatty acid oxidation of pressure-overloaded hearts. As in the case of statins, the compound appears to have a pleiotropic action. As a consequence of CPT I inhibition, cytoplasmic triacylglycerols and fatty acids are increased and thereby provide additional endogenous PPAR
ligands, leading to activation of the important transcription factor PPAR. Because of its fatty acid residue, etomoxir is also expected to be a direct ligand for PPAR. In contrast to established PPAR agonists such as the hypolipidemic fibrates, which increase fatty acid oxidation, etomoxir leads to PPAR activation without increasing fatty acid oxidation; i.e., it belongs to the drug class of "fatty acid oxidation inhibitors with PPAR activation (FOXIB/PPAR)" exhibiting a dual mechanism of action. In this respect, an intriguing observation of Lionetti et al. [7] was the marked upregulation of pyruvate dehydrogenase kinase-4 (PDK-4) mRNA, which is a typical response to PPAR activation. However, PPAR activation on its own with an established PPAR agonist had detrimental effects in the pressure-overloaded heart [9]. The dose used was high enough to counteract the reduction of fatty acid oxidation of the pressure-overloaded heart and actually appeared to enhance fatty acid oxidation beyond control values [9].
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Chronic etomoxir treatment rescued the down-regulated SERCA2 of hypertrophied, pressure-overloaded hearts back to near normal levels. The SR Ca2+ ATPase activity, Ca2+ uptake rate, number of active Ca2+ pumps [E
P] and SERCA2 protein and mRNA abundance were increased (see Refs. [10,11] and references therein). Since a reduction in SERCA2 expression results in an impaired Ca2+ handling by the cardiomyocyte, it appears to be a causative defect leading to depression of pump function. Etomoxir also increased the proportion of -MHC or myosin V1 (2 -MHC), demonstrating a coordinated expression of genes required for fast relaxation and contraction of the heart. Based on putative regulatory sequences on the SERCA2 promoter, the transcriptional effects of etomoxir have been attributed to a shift in energy metabolism with increased glucose utilization and/or PPAR activation [11]. The etomoxir-induced increase in gene expression of SERCA2 and -MHC was associated with an improved pump function of the pressure-overloaded heart [8]. Since the high afterload arising from constriction of the ascending aorta cannot be reduced by a drug, direct actions on the cardiomyocyte have to be inferred. At low dosage, etomoxir had a selective influence on the pressure-overloaded left ventricle. Both myocardial working capacity and rates of contraction and relaxation of isovolumically beating hearts were increased. Etomoxir also influenced the transition from apparently compensated to decompensated cardiac hypertrophy [12]. After severe constriction of the ascending aorta, the pronounced left ventricular hypertrophy was associated with pulmonary congestion indicating heart failure. The SR Ca2+ uptake rate per gram wet weight was reduced, which was independent of phospholamban phosphorylation and the inhibition of the SR Ca2+ release mechanism. The SERCA2 protein amount was likewise reduced. The SR Ca2+ uptake rate was inversely correlated with left ventricular weight, but was not influenced by the occurrence of pulmonary edema. Since the calculated SR Ca2+ uptake rate of the whole ventricle was not reduced, a hypertrophy proportional dilution of SR Ca2+ pumps that precedes the occurrence of pulmonary edema appears likely. Etomoxir did not affect left ventricular weight, but reduced right ventricular hypertrophy, which is a consequence of pulmonary edema. In parallel, the SR Ca2+ uptake rate and the proportion of myosin V1 increased. It was concluded that etomoxir represents a candidate drug for the prevention of heart failure progression by increasing the SR Ca2+ uptake rate. In accordance, selective restoration of SERCA2 by adenoviral gene transfer resulted in functional improvement in pressure overload-induced heart failure and normalization of 51 gene transcripts [3], demonstrating the occurrence of compensatory reprogramming of gene expression as a result of impaired function. |
4. CPT I inhibition in patients with heart failure |
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Top1. Gene expression of...2. Oxfenicine treatment in...3. Etomoxir counteracts a...4. CPT I inhibition...References |
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Heart failure is a disease with many causes and one cannot simply extrapolate from animal experiments to heart failure in general. Nonetheless, the study by Lionetti et al. [7] is unique because it demonstrates its effects in a large-animal model of severe heart failure, which follows a predictable time course of transition to decompensation. Thus, compounds referred to as CPT I inhibitors represent not only an effective therapy for heart failure in rat models. Based on the animal experiments, clinical trials in heart failure appear to be a rational consequence.
In a pilot study on etomoxir in 10 patients with impaired heart performance but without diabetes mellitus type II, an improved cardiac function was observed after a 3-month treatment [13]. Based on echocardiographic data, it was concluded that the etomoxir treatment had no influence on left ventricular muscle mass. Also, no significant side effects were observed. In acute studies, etomoxir showed neither a positive inotropic effect nor vasodilatory properties [13]. A randomized, placebo-controlled trial including heart failure patients of NYHA classes II–III with no metabolic or other severe diseases was terminated prematurely, however, because side effects had occurred in a small number of patients.
Should this drug approach be pursued further? The observed adverse events do not argue against the validity of basic mechanisms underlying the beneficial effects observed in the dog and rat. One should, however, take into account that irreversible CPT I inhibition has its risks if the dosage cannot be maintained due to an impaired drug elimination. Obviously, excessive CPT I inhibition has adverse consequences. Thus, etomoxir can cause lipid accumulation in the rat liver [14]: 125 mg/kg/day of active enantiomeric (+)-etomoxir was administered, which is much higher than the dose [15 mg/kg/day racemic (±)-etomoxir corresponding to 7.5 mg/kg/day of active (+)-form] with selective effects in overloaded rat hearts and which only moderately increased lipid droplets in the heart [10]. Lipid accumulation due to CPT I inhibition is expected to be counteracted by the hypolipidemic action of etomoxir [15] arising from a reduced de novo fatty acid synthesis. In future trials, therefore, blood levels of CPT I inhibitors should be determined to detect accumulation of the compound due to possible drug interactions.
In summary, the study by Lionetti et al. [7] represents another important step in the search for drugs that not only interfere with neuroendocrine activation but target defects within the overloaded or failing cardiomyocyte. Such studies also help in dealing with the misconception that heart failure is just a symptom and not a disease on its own with causative changes within the cardiomyocytes. Efforts should be strengthened to assess signals associated with cardiac energy metabolism for their potential of correcting a dysregulated phenotype of overloaded and failing cardiomyocytes. In particular, studies on promoter interactions of SERCA2 and related genes involving Ca2+ in addition to metabolic signals [11,16] are required for further drug screening. Restoring the function of hypertrophied cardiomyocytes during early asymptomatic progression of heart failure would be of particular relevance in elderly patients with inadequately treated hypertension.
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