The transcriptome of human epicardial, mediastinal and subcutaneous adipose tissues in men with coronary artery disease

Abstract

Background: The biological functions of epicardial adipose tissue (EAT) remain largely unknown. However, the proximity of EAT to the coronary arteries suggests a role in the pathogenesis of coronary artery disease (CAD). The objectives of this study were to identify genes differentially regulated among three adipose tissues, namely EAT, mediastinal (MAT) and subcutaneous (SAT) and to study their possible relationships with the development of cardiovascular diseases.

Methods and results: Samples were collected from subjects undergoing coronary artery bypass grafting surgeries. Gene expression was evaluated in the three adipose depots of six men using the Illumina® HumanWG-6 v3.0 expression BeadChips. Twenty-three and 73 genes were differentially up-regulated in EAT compared to MAT and SAT, respectively. Ninety-four genes were down-regulated in EAT compared to SAT. However, none were significantly down-regulated in EAT compared to MAT. More specifically, the expression of the adenosine A1 receptor (ADORA1), involved in myocardial ischemia, was significantly up-regulated in EAT. Levels of the prostaglandin D2 synthase (PTGDS) gene, recently associated with the progression of atherosclerosis, were significantly different in the three pairwise comparisons (EAT>MAT>SAT). The results of ADORA1 and PTGDS were confirmed by quantitative real-time PCR in 25 independent subjects.

Conclusions: Overall, the transcriptional profiles of EAT and MAT were similar compared to the SAT. Despite this similarity, two genes involved in cardiovascular diseases, ADORA1 and PTGDS, were differentially up-regulated in EAT. These results provide insights about the biology of EAT and its potential implication in CAD.

Figure 1. Heat map of the top 10 genes differentially up- and down-regulated for the three pairwise comparisons.

The samples and genes are illustrated in columns and rows, respectively. Red and green represent high and low expression, respectively. The full names and biological processes related with these genes are provided in Tables S4, S5, and S6.

Figure 2. Cardiovascular functions linked to up-regulated genes in EAT compared to MAT.

ACSL1, Acyl-CoA synthetase long-chain family member 1; ADORA1, adenosine A1 receptor; HSD17B1, hydroxysteroid (17-beta) dehydrogenase 1; MGP, matrix Gla protein; NMB, neuromedin B; PTGDS, prostaglandin D2 synthase; SERPINA5, serpin peptidase inhibitor -clade A (alpha-1 antiproteinase, antitrypsin)- member 5; and SOX9, SRY (sex determining region Y)-box 9. *Interaction with itself. →Acts on.

Figure 3. Cardiovascular functions linked to up- (red) and down-regulated (green) genes in EAT compared to SAT.

ACTG2, actin, gamma 2, smooth muscle, enteric; ADRA2A, adrenergic, alpha-2A-, receptor; AMPH amphiphysin; BCHE, butyrylcholinesterase; C6, complement component 6; CBS, cystathionine-beta-synthase; CNTNAP2, contactin associated protein-like 2; COL3A1, collagen, type III, alpha 1; COL12A1, collagen, type XII, alpha 1; CTSG, cathepsin G; CXCR4, chemokine (C-X-C motif) receptor 4; FRAS1, Fraser syndrome 1; MAOB, monoamine oxidase B; MARCKSL1, MARCKS-like 1; MYH11, myosin, heavy chain 11, smooth muscle; NOX4, NADPH oxidase 4; NTRK2, neurotrophic tyrosine kinase, receptor, type 2; PAMR1, peptidase domain containing associated with muscle regeneration 1; PDE1A, phosphodiesterase 1A calmodulin-dependent; RARB, retinoic acid receptor beta; SEMA3C, sema domain, immunoglobulin domain (Ig), short basic domain, secreted, (semaphorin) 3C; and SERPINE2, serpin peptidase inhibitor clade E (nexin, plasminogen activator inhibitor type 1), member 2. *Interaction with itself.

Figure 4. Comparison of fold changes for ADORA1, ADRA2A, LIPE, and PTGDS.

EAT vs MAT (A), EAT vs SAT (B) and MAT vs SAT (C). The red bars represent the fold changes obtained by microarrays. The green and violet bars represent the fold changes obtained by qPCR for the microarrays and qPCR subjects, respectively. †Significant in the microarray experiment. *p<0.05, **p<0.001, and ***p<0.0001.