Pericardial Adipose Tissue Thrombospondin-1 Associates With Antiangiogenesis in Ischemic Heart Disease

Abstract

Accumulation of ectopic pericardial adipose tissue has been associated with cardiovascular complications which, in part, may relate to adipose-derived factors that regulate vascular responses and angiogenesis. We sought to characterize adipose tissue microvascular angiogenic capacity in individuals undergoing elective cardiac surgeries including aortic, valvular, and coronary artery bypass grafting. Pericardial adipose tissue was collected intraoperatively and examined for angiogenic capacity. Capillary sprouting was significantly blunted (2-fold, p<0.001) in subjects with CAD (age 60±9 years, BMI 32±4 kg/m2, LDL-C 95±46 mg/dl, n=29) compared to age-, BMI-, and LDL-C matched individuals without angiographic obstructive CAD (age 59±10 years, BMI 35±9 kg/m2, LDL-C 101±40 mg/dl, n=12). For potential mechanistic insight, we performed mRNA expression analyses using quantitative RT- PCR, and observed no significant differences in pericardial fat gene expression of pro-angiogenic mediators vascular endothelial growth factor-A (VEGF-A), fibroblast growth factor-2 (FGF-2), and angiopoietin-1 (angpt1), or anti-angiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and endostatin. In contrast, mRNA expression of anti-angiogenic thrombospondin-1 (TSP-1) was significantly upregulated (2-fold, p=0.008) in CAD compared to non-CAD subjects, which was confirmed by protein western-immunoblot analysis. TSP-1 gene knockdown using shRNA lentiviral delivery significantly improved angiogenic deficiency in CAD (p<0.05). In conclusion, pericardial fat in subjects with CAD may be associated with an anti-angiogenic profile linked to functional defects in vascularization capacity. Local paracrine actions of TSP-1 in adipose depots surrounding the heart may play a role in mechanisms of ischemic heart disease.