Program in Molecular Medicine; Department of Surgery, Division of Cardiothoracic Surgery; Department of Medicine, Division of Cardiovascular Medicine
Medical Subject Headings
Integrins; Adipose Tissue; Coronary Artery Disease; Transforming Growth Factor beta; Gene Expression; Inflammation
Amino Acids, Peptides, and Proteins | Biochemistry, Biophysics, and Structural Biology | Cardiology | Cardiovascular Diseases
Background: In patients with coronary artery disease (CAD), epicardial adipose tissue (EAT) has been shown to express increased levels of inflammatory cytokines (IL-1β, IL-6, MCP-1, TNFα) and decreased levels of anti-inflammatory and cardioprotective adipokines. However, it is not known whether or not inflammation in EAT is a primary cause or a secondary response to atherosclerosis. In order to better understand this pathophysiology, we tested the hypothesis that expression of certain genes in EAT would correlate with the degree of coronary atherosclerosis.
Purpose: The purpose of this study was to determine whether there is a difference in gene expression in epicardial fat of patients with and without coronary artery disease and if there is a difference, whether these differentially expressed genes participate in the inflammatory pathways.
Methods: EAT and paired subcutaneous adipose tissue (SAT) samples collected from cardiac surgery patients with and without coronary disease were fixed for microscopy and frozen for RNA extraction. RNA was hybridized to Affymetrix Human Gene 1.0 ST chips. We used an unbiased approach to identify genes highly and differentially expressed in EAT vs. SAT (FC>3.0). The probe intensities for these resultant genes were then correlated with the severity of atherosclerosis in each patient as determined by the Gensini score.
Results: 35 genes were differentially expressed in EAT at >3.0 fold change (p<0.05). Of these, 14 genes were significantly correlated with the degree of atherosclerosis, quantified by Gensini score. Integrin αvβ8 (ITGB8) and transglutaminase 2 (TGM2) were both more highly expressed in EAT than in SAT (p<0.009) for all patients. Expression of ITGB8 had the strongest positive correlation (r=0.94, p<0.01), while TGM2 had the strongest negative correlation (r=-0.80, p<0.01) (Fig. 1). Importantly, expression of neither ITGB8 nor TG2 in SAT correlated with the extent of atherosclerosis.
Conclusions: Using an unbiased whole genome approach, we identified ITGB8 and TG2 as genes whose expression is correlated with CAD severity. ITGB8 has been previously shown to be expressed by fibroblasts and functions to activate TGFβ. TGFβ signaling has also been correlated with advanced atherosclerosis. We speculate that EAT expression of ITGB8 may have pro-inflammatory effects, possibly by activating TGFβ, and stimulating recruitment of dendritic cells or T cells to secondary lymphoid organs in EAT. Whether or not this is the case is a goal of future studies.
Lee, Nancy; Nicoloro, Sarah M.; Straubhaar, Juerg R.; Darrigo, Melinda; Tam, Stanley; Czech, Michael P.; and Fitzgibbons, Timothy P., "Expression of ITGB8 in Epicardial Adipose Tissue is Highly and Directly Correlated with the Severity of Coronary Atherosclerosis" (2013). University of Massachusetts Medical School. Senior Scholars Program. Paper 152.