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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online August 2, 2004 as doi:10.1096/fj.03-1242fje. |
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* Unité de recherches sur les obésités, Institut National de la Santé et de la Recherche Médicale (Inserm U586), Institut Louis Bugnard, Centre Hospitalier Universitaire de Toulouse, Université Paul Sabatier, Toulouse, France; and
Department of Cardiovascular Surgery and
Department of Cardiology, Toulouse University Hospital, Toulouse, France
1Correspondence: INSERM U586, Faculté de Médecine, Laboratoire de Pharmacologie Médicale et Clinique, 37 Allées Jules Guesde. 31073 Toulouse cedex, France. E-mail: Philippe.rouet{at}toulouse.inserm.fr
A dramatic increase in the prevalence of obesity and cardiovascular morbidity is expected in the coming years for most countries. However, little is known about the specific contribution of obesity to (associated) cardiovascular morbidity. Molecular mechanisms of heart adaptation to obesity so far have not been investigated.
SPECIFIC AIMS
We aimed to define the specific cardiac alterations detectable at the molecular level in the obese human heart and in hearts from patients suffering from obesity-related hypertension or arterial hypertension. These molecular adaptations were expected to be specific and indicative of cardiac function and remodeling.
PRINCIPAL FINDINGS
1. Statistical analysis of the data revealed 2686 differentially expressed genes of 11,500 tested when compared with control tissues
Differential expression was verified by real-time PCR in 84% of 50 randomly chosen genes. Among the genes encountered, 397 were specifically regulated in obese (O), 1299 in non-obese hypertensive (H), and 355 in obese hypertensive patients (OH); an additional set of 153 genes was differentially expressed in all these situations. Since the cDNA arrays also comprised cDNA encoding for unknown proteins, genes encoding 16 new putative secreted and 29 DNA binding proteins regulated in the O or OH group were identified. Novel heart secreted proteins could represent early plasmatic markers of cardiac remodeling or failure.
2. Ontology analysis was performed focusing on eight gene categories for each patient group
The profile of gene adaptation in hearts of patients from group O is qualitatively different from that observed in patients from OH and H groups. The changes in genes encoding secreted proteins, inflammation, apoptosis, or extracellular matrix-related proteins were better represented in hearts from group O.
3. Hierarchical clustering grouped obese hypertensive patients’ gene expression profile apart from the obese or hypertensive group, indicating that this phenotype is specific
Heart gene expression profiles differed greatly between each category of patients, unequivocally confirming each patient’s group. Therefore, obesity, obesity-related hypertension, and arterial hypertension can be regarded as major regulators of the cardiac transcriptome.
4. Pathway analysis using GenMapp clearly showed that the Wnt pathway, known to be involved in cardiac hypertrophy mechanisms, showed opposite regulation in obese heart vs. hypertensive heart and potentially prevented the development of cardiac remodeling in obese patients
CONCLUSIONS AND SIGNIFICANCE
This is the first time the human heart transcriptome has been studied in obese or obese hypertensive patients. No indications about the molecular mechanism underlying the cardiac remodeling that occurs in the hearts from such patients was available. This information could explain the increased prevalence of cardiac events (arrhythmias, heart failure, etc.). We found that arterial hypertension up-regulates the entire Wnt pathway whereas this pathway is down-regulated in obese patients. This observation may explain the differences observed in cardiac remodeling and, more generally, the cardiovascular outcome of these two types of patients.
Obesity, obesity-related hypertension, and hypertension are more potent and preponderant regulators of the cardiac transcriptome than heterogeneous genetic backgrounds and patient history.
From a global point of view, this analysis indicates dramatic changes in the pattern of expression in the heart between controls and each patient group. The pattern of regulation in O and OH groups was clearly different from that observed in patients from group H. Clustering analysis also shows that the pattern of heart gene expression in OH patients is very specific and not the result of additive effects of arterial hypertension and obesity. The latter observation raises a new concept and opposes the current view that gene regulation in obesity-related hypertension is the combined sum of obesity and arterial hypertension.
This work shows that uncomplicated obesity has a strong effect on cardiac gene expression that could be considered a precursor for future cardiac disease. We propose that obesity-related hypertension has a particular molecular picture in the heart and that these data could help develop adapted treatment for obese hypertensive patients.
To complement this transcriptome study, development of cardiac proteome analysis should further elucidate molecular cardiac adaptation in obesity or obesity-related hypertension and could generate new early clinical markers of disease or new putative pharmaceutical targets to prevent cardiac failure and sudden death.
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FOOTNOTES
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.03-1242fje;
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