(Circulation. 2002;105:1025.)
© 2002 American Heart Association, Inc.
Editorial |
Peroxisome Proliferator-Activated Receptor 
as a Genetic Determinant of Cardiac Hypertrophic Growth
Culprit or Innocent Bystander?
From the Center for Cardiovascular Research, Departments of Medicine, Molecular Biology and Pharmacology, and Pediatrics, Washington University School of Medicine, St Louis, Mo.
Correspondence to Daniel P. Kelly, MD, Center for Cardiovascular Research, Washington University School of Medicine, 660 S Euclid Ave, Campus Box 8086, St Louis, MO 63110. E-mail dkelly{at}imgate.wustl.edu
Key Words: Editorials • hypertrophy • metabolism • genetics • hormones
Left ventricular hypertrophy (LVH) occurs in response to a long-term increase in hemodynamic load related to a variety of physiological and pathophysiological conditions. The cardiac hypertrophic response is considered to be purely adaptive during postnatal growth stages and in response to exercise training. In contrast, pathological forms of LVH, such as that caused by hypertension, often enter a phase of pathological remodeling that leads to contractile dysfunction and ultimately to heart failure. These observations suggest that certain components of the pathological cardiac hypertrophic response are maladaptive, contributing to a pathological remodeling response. Previous studies have demonstrated that left ventricular (LV) mass is a risk factor for future cardiac events in patients with pathological forms of LVH.1,2 Of interest is the fact that clinical studies also have revealed significant variability in LV mass, independent of blood pressure, among individuals with LVH, suggesting that the hypertrophic response is influenced by genetic and environmental factors.3,4
See Circulation. 2002;105:950–955.
Peroxisome Proliferator-Activated Receptor 
Gene as a Candidate Determinant of the Ventricular Hypertrophic Growth Response
Despite evidence for genetic determinants of the LVH phenotype in humans, little is known about the specific genes involved. The results of previous studies have suggested a role for the angiotensin-converting enzyme (ACE) insertion/deletion genotype as a predictor of the cardiac hypertrophic response.5,6 Hypertrophic cardiomyopathy is caused by mutations in genes encoding a variety of sarcomeric proteins, providing another potential genetic link.7 However, convincing evidence for genetic modifiers of the ventricular hypertrophic response due to common diseases such as hypertension generally is lacking.
In the February 26, 2002, issue of Circulation, the report by Jamshidi et al8 demonstrates a potential link between the gene encoding the peroxisome proliferator-activated receptor (PPAR) and the magnitude of LVH in humans. Jamshidi et al8 found that a single-nucleotide polymorphism within intron 7 of the PPAR gene (PPAR-GC) was significantly associated with the degree of physiological LVH in a cohort of healthy white male British Army volunteers randomly assigned to receive losartan during a vigorous 10-week exercise program. At the end of the training period, LV mass was significantly greater in subjects with the PPAR-CC genotype than in those in the PPAR-GG group. The influence of the PPAR-CC genotype on the degree of LVH was independent of losartan treatment and ACE genotype. A second known PPAR gene variant, L162V, did not independently influence LV mass but attenuated the effect of the PPAR-C allele. In a separate cohort of subjects with hypertension, Jamshidi et al8 found that the PPAR-C allele was significantly associated with LV mass in men but not women, an effect that was independent of blood pressure. Collectively, these results identify the PPAR-C allele as a potential marker of the cardiac hypertrophic growth response and the PPAR gene as a candidate modifier of the LVH phenotype in humans.
PPAR, Myocardial Metabolism, and Cardiac Hypertrophy: What Is the Link?
Is there a link between PPAR and the cardiac hypertrophic growth program? To address this question, it is useful to first consider the biological and physiological roles of PPAR in the heart. PPAR, along with PPARß (
) and PPAR
, comprise a subgroup within the nuclear receptor transcription factor superfamily. PPARs bind to cognate DNA sequences in target gene regulatory regions as a heterodimer with the retinoid X receptor (RXR) (reviewed in reference 9).9 PPAR is enriched in tissues with a high capacity for fatty acid oxidation (FAO), such as heart, liver, brown adipose, and slow-twitch skeletal muscle. It was first described as a regulator of peroxisomal FAO but is now known to regulate the expression of genes involved in every step of cellular fatty acid utilization, including fatty acid import, thioesterification, and mitochondrial FAO. In contrast, PPAR is adipose enriched and controls programs involved in fat storage. The functional role of the ubiquitously expressed PPARß is not well understood. As a nuclear receptor, PPAR is ligand activated. Its list of potential ligands is long, including fibric acid derivatives and other peroxisome proliferators, certain eicosanoid derivatives, and long-chain fatty acid moieties. The true endogenous PPAR ligands have not been clearly defined, although fatty acid derivatives would seem to be the best candidates, particularly in the heart where this nuclear receptor drives the high level expression of genes involved in the oxidation of fatty acids to meet energy demands. Studies performed with PPAR-null mice have demonstrated the importance of PPAR in the maintenance of a high-capacity mitochondrial FAO system in heart (reviewed in reference 10).10 In contrast to the normal postnatal mammalian heart, which relies heavily on fatty acids for energy production, the PPAR-null heart exhibits markedly reduced FAO rates and a corresponding increase in glucose utilization.11 Mice lacking PPAR are unable to maintain cardiac lipid and energy homeostasis under conditions of metabolic stress. For example, fasting or pharmacological inhibition of FAO leads to myocardial lipid accumulation and hypoglycemia in PPAR-null mice, an effect that is more pronounced in male than in female animals. Thus, PPAR plays a critical role in cardiac energy and lipid homeostasis.
Is the role of PPAR as a regulator of cardiac energy metabolism related to cardiac hypertrophy? Several lines of evidence link alterations in cardiac energy metabolism, especially the mitochondrial FAO pathway, to cardiac hypertrophy. First, genetic defects in several energy transduction/production pathways cause hypertrophic forms of cardiomyopathy. For example, children with inborn errors in FAO enzymes often exhibit LVH.12 Nuclear and mitochondrial genome mutations that cause mitochondrial respiratory dysfunction also may cause cardiac hypertrophy.13 Recently, a form of inherited hypertrophic cardiomyopathy was mapped to the gene encoding a regulatory subunit of adenosine monophosphate-activated protein kinase (AMPK).14,15 AMPK is a critical regulator of FAO in the heart. Second, pharmacological inhibition of the cardiac mitochondrial FAO pathway leads to cardiac hypertrophy.16 Third, studies performed in a variety of mammalian organisms, including humans, have shown that during pressure overload-induced cardiac hypertrophic growth, the expression of FAO enzymes is reduced, leading to a fall in myocardial FAO rates and an increase in glucose utilization (reviewed in references 10 and 17).10,17
Are the metabolic derangements associated with cardiac hypertrophy related to the PPAR gene regulatory pathway? Recent evidence indicates that the myocardial energy substrate shift away from FAO is due, at least in part, to a reduction in the PPAR-mediated expression of genes involved in cardiac mitochondrial FAO.18–20 Studies performed in rodent models of pressure overload and with cardiac myocytes in culture have shown that activity of the PPAR gene regulatory pathway is reduced at several levels during hypertrophic growth. Within hours of exposure to a hypertrophic stimulus, the activity of PPAR within the cardiac myocyte is diminished via phosphorylation mediated by the extracellular signal-regulated kinase mitogen-activated protein kinase (ERK-MAPK) pathway.21 The short-term effect of ERK-MAPK on PPAR activity is followed by a long-term decrease in PPAR gene expression if the hypertrophic growth stimulus (eg, pressure overload) is maintained.18–20 Coincident with the reduction of PPAR expression and activity, the expression of a known transcriptional repressor of PPAR target genes, chicken ovalbumin upstream promoter-transcription factor (COUP-TF), increases in the hypertrophied heart, further contributing to the suppression of FAO enzyme gene expession.19 These collective results demonstrate a strong association between the pathological cardiac hypertrophic growth response and a reduction in PPAR-mediated control of myocardial energy metabolism.
The results described above suggest that PPAR may be linked to cardiac hypertrophic growth via derangements in myocardial metabolism. Is this a cause-effect relationship or an association related to secondary effects? The observations that genetic or pharmacological inhibition of mitochondrial FAO leads to ventricular hypertrophy strongly suggests that a reduction in myocardial fatty acid utilization is a primary trigger for cardiac growth. However, the mechanistic links remain unknown. It is possible that deactivation of PPAR or activation of its antagonist, COUP-TF, leads directly to myocyte growth through as yet unidentified target genes. Alternatively, the metabolic shifts per se may be involved. For example, reduced flux through FAO pathways or increased glucose utilization may lead to a growth response via metabolic signals. Intracellular lipid moieties are excellent candidates for mediating metabolic signals leading to myocyte growth. A reduction in capacity for myocyte fatty acid catabolism within the mitochondrion could lead to an increase in upstream lipid intermediates capable of activating cellular signaling pathways linked to myocyte growth pathways. In support of this notion, a recent study demonstrated that transgenic mice with increased myocardial uptake of fatty acids because of overexpression of fatty acyl-CoA synthetase exhibit ventricular hypertrophy.22 The identity of the putative lipid-triggered myocyte signaling pathways remain unknown.
Truth or Consequence?
The provocative findings of the Jamshidi study8 have identified a candidate genetic determinant of the cardiac hypertrophic response in humans. However, the results fall short of defining a primary link between the human PPAR gene and the cardiac hypertrophic response for the following reasons. First, as described above, despite ample evidence that alterations in cardiac energy substrate utilization and PPAR activity are tightly associated with pathological forms of ventricular hypertrophy, convincing evidence for a cause-effect relationship is lacking. Second, the study does not address the relative expression of the PPAR-GC alleles. Accordingly, the mechanism whereby the polymorphisms may influence the expression of the PPAR gene is not clear. As suggested by the authors, it is possible that the intronic polymorphisms affect PPAR gene expression through linkage with upstream promoter region variants. However, it is also possible that the GC alleles are linked to a separate relevant gene located in the vicinity of the PPAR gene. It is of interest, however, that the functional PPAR coding region variant, V162, which is known to affect PPAR activity, was found to attenuate the influence of the PPAR-C allele on exercise-induced LVH. Third, the PPAR-C allele was shown to be associated with increased LV mass in response to both pathological and physiological stimuli. However, downregulation of the FAO pathway is believed to occur only with pathological forms of LVH. Finally, given that PPAR is expressed in a variety of tissues, including the liver and kidney, the observed results could be due to secondary effects on whole body metabolism or circulating levels of factors with cardiac growth-promoting activity. Future studies aimed at the evaluation of cardiac metabolism in humans with distinct PPAR-GC haplotypes and analysis of the expression and activity of the PPAR-GC variants will be necessary to determine whether the PPAR gene is a true modifier of the cardiac hypertrophic growth phenotype.
Conclusions: A Plethora of New Questions
In summary, the study by Jamshidi et al8 has identified the human PPAR gene as a new candidate genetic modifier of the cardiac hypertrophic response. These results are exciting despite the fact that a cause-effect relationship has not yet been established. A hallmark of an important descriptive study is that it raises more questions than answers. The Jamshidi study8 meets this criterion. Among the many questions raised by this study are (1) What is the significance of the observed sex difference in the association between the PPAR-C allele and LVH in hypertensive subjects? As suggested by the authors, it is tempting to speculate that the sex difference relates to the observation that male mice lacking PPAR show a more pronounced phenotype than do female mice. (2) Does the PPAR-C allele identify individuals with LVH at increased risk for progression to pathological remodeling and heart failure? Jamshidi et al8 did not address this question. However, the surprising observation that LV mass was greater in individuals with the PPAR-C allele in the context of both physiological and pathological hypertrophy indicates that this marker may not be predictive of a pathological outcome. (3) Is PPAR a target for the development of new therapeutic approaches for patients with pathological forms of LVH at risk for developing heart failure? PPAR agonists with relatively weak cardiac activity (eg, gemfibrozil) already exist as hypolipidemic agents. However, before evaluation of PPAR agonists for use as treatment of patients with pathological LVH begins, the role of altered PPAR activity in the treatment of hypertrophied heart as adaptive or maladaptive must be defined. (4) Are other components of the PPAR transcriptional regulatory complex, such as the nuclear receptor RXR, modifiers of the cardiac hypertrophic response? The answers to these questions await future studies as we enter a new era of clinical research involving the application of genomics and genotype-phenotype analyses to common cardiovascular diseases.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
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