Kinetic analysis of cardiac transcriptome regulation during chronic high-fat diet in dogs

Abstract

Rouet. Kinetic analysis of cardiac transcriptome regulation during chronic high-fat diet in dogs. Physiol Genomics 19: 32-40, 2004. First published June 29, 2004 doi:10.1152/physiolgenomics.00001.2004In the present study, we investigated, using custom dog cDNA arrays, the time course of transcriptional changes in the left ventricle of dogs fed a normal diet or a high-fat diet (HFD) for 9-24 wk. Array hybridizations were performed with complex probes representing mRNAs expressed in left ventricles from obese hypertensive and lean control dogs. We identified 63 differentially expressed genes, and expression of 17 of 20 randomly chosen genes was confirmed by real-time PCR. Transcripts were categorized into groups involved in metabolism, cell signaling, tissue remodeling, ionic regulation, cell proliferation, and protein synthesis. Hierarchical clustering indicated that the pattern of coregulated genes depends on duration of the HFD, suggesting that HFD-induced obesity hypertension is associated with continuous cardiac transcriptome adaptation despite stability of both body weight and blood pressure. GenMAPP analysis of the data pointed out the crucial importance of the ventricle TGF-␤ pathway. Our results suggest that this system may be involved in molecular remodeling during HFD and in changes observed in the transcription profile, reflecting functional and morphological abnormalities that arise during prolonged HFD. These results also suggest some novel regulatory pathways for cardiac adaptation to obesity. hypertension; obesity; functional genomics; hypertension; arrays; heart OBESITY IS HIGHLY PREVALENT in developed countries and will be a major health concern in the future mainly because of its impact on cardiovascular morbidity and mortality (22,27,35,49). Duration of obesity has been shown to be a determinant of the incidence and severity of obesity-associated cardiac morbidity (4, 36), raising the probability that the recent increase in prevalence of childhood obesity will in the future result in a marked rise in the appearance of cardiovascular diseases (14,34,44). Cardiovascular morbidity in obesity is, in part, a consequence of arterial hypertension (33) as well as endocrine and metabolic disorders such as insulin resistance, diabetes mellitus, or dyslipidemia. However, increased adiposity enhances secretion of multiple adipokines (53) that may act on target organs such as kidney, brain, and heart (19).Our group and others have investigated the cardiovascular adaptations to obesity in dogs fed a hyperlipidic, hypercaloric diet (HFD) (17,43,54). This model closely mimics human obesity and is associated with hypertension, cardiac dysfunction, and metabolic abnormalities. This is in contrast to many mouse and rat genetic models of obesity with defects in leptin synthesis or leptin signaling. In most of these models obesity is not associated with sympathetic nervous system activation or hypertension. Moreover, dietary models of obesity, especially those produced by feeding an HFD, mimic the diet of Western ...

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“…In our previous obese heart transcriptome analysis (23,24), we had identified a set of 63 differentially expressed genes, and 11 cDNA sequences representative of mRNAs coding for new proteins of unknown functions were found to be differentially expressed in atria after 9 weeks of high fat diet (23). One cDNA that was already present in expressed cDNA data bases was found to encode for a potentially new putative secreted protein.…”

“…We and others developed a dog nutritional model of obesity using a hypercaloric high fat diet (21,22) in which we recently showed early and late specific gene regulations at the transcriptome level in heart from these animals (23,24). Differentially expressed genes, when compared with regular fed animals, were categorized into groups involved in metabolism, cell signaling, ionic regulation, cell proliferation, protein synthesis, and tissue remodeling.…”

Functional Genomics of Cardioprotection by Ischemic Conditioning and the Influence of Comorbid Conditions: Implications in Target Identification

“…In a following study, they studied temporal changes in gene expression as well. Dogs were fed with high-fat chow for 9-24 weeks and left ventricular mRNA levels were assessed by microarrays [31]. In these experiments they identified a timedependent decrease in the ventricular expression of phospholamban and SERCA-2.…”

European Society of Hypertension Working Group on Obesity Obesity-induced hypertension and target organ damage: current knowledge and future directions

“…These structural changes, which are also likely to be influenced by increased TGF-b expression, fibrosis, and impaired b-adrenergic receptor signaling [49,50], result in progressive impairment of left ventricular filling and, subsequently, diastolic heart failure. In fact, obesity has been identified as an independent predictor of left ventricle (LV) diastolic dysfunction in the general population [51].…”