Ahmed Bulbul, Farb Melissa G, Karki Shakun, D'Alessandro Sophia, Edwards Niloo M, Gokce Noyan
Evans Department of Medicine, Boston University School of Medicine, Boston, Massachusetts; Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts.
Division of Cardiac Surgery, Boston Medical Center, Boston, Massachusetts.
Am J Cardiol. 2024 Jan 1;210:201-207. doi: 10.1016/j.amjcard.2023.09.104. Epub 2023 Oct 18.
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 subjects who underwent 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 (twofold, p <0.001) in subjects with coronary artery disease (CAD) (age 60 ± 9 years, body mass index [BMI] 32 ± 4 kg/m, low-density lipoprotein cholesterol [LDL-C] 95 ± 46 mg/100 ml, n = 29) compared with age-, BMI-, and LDL-C matched subjects without angiographic obstructive CAD (age 59 ± 10 y, BMI 35 ± 9 kg/m, LDL-C 101 ± 40 mg/100 ml, n = 12). For potential mechanistic insight, we performed mRNA expression analyses using quantitative real-time polymerase chain reaction and observed no significant differences in pericardial fat gene expression of proangiogenic 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 (twofold, p = 0.008) in CAD compared with non-CAD subjects, which was confirmed by protein western-immunoblot analysis. TSP-1 gene knockdown using short hairpin RNA lentiviral delivery significantly improved angiogenic deficiency in CAD (p <0.05). In conclusion, pericardial fat in subjects with CAD may be associated with an antiangiogenic 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.
异位心包脂肪组织的蓄积与心血管并发症有关，这在一定程度上可能与调节血管反应和血管生成的脂肪衍生因子有关。我们试图对接受择期心脏手术（包括主动脉、瓣膜和冠状动脉搭桥术）的受试者的脂肪组织微血管血管生成能力进行表征。术中收集心包脂肪组织并检测其血管生成能力。与年龄、体重指数（BMI）和低密度脂蛋白胆固醇（LDL-C）匹配的无血管造影阻塞性冠心病的受试者（年龄59±10岁，BMI 35±9kg/m²，LDL-C 101±40mg/100ml，n = 12）相比，冠状动脉疾病（CAD）患者（年龄60±9岁，BMI 32±4kg/m²，LDL-C 95±46mg/100ml，n = 29）的毛细血管芽生明显减弱（两倍，p<0.001）。为了获得潜在的机制性见解，我们使用定量实时聚合酶链反应进行mRNA表达分析，并未观察到促血管生成介质血管内皮生长因子-A（VEGF-A）、成纤维细胞生长因子-2（FGF-2）和血管生成素-1（angpt1），或抗血管生成因子可溶性fms样酪氨酸激酶-1（sFlt-1）和内皮抑素在心包脂肪基因表达上有显著差异。相比之下，与非CAD受试者相比，CAD患者中抗血管生成的血小板反应蛋白-1（TSP-1）的mRNA表达显著上调（两倍，p = 0.008），蛋白质免疫印迹分析证实了这一点。使用短发夹RNA慢病毒递送敲低TSP-1基因可显著改善CAD患者的血管生成缺陷（p<0.05）。总之，CAD患者的心包脂肪可能与血管生成功能缺陷相关的抗血管生成特征有关。TSP-1在心脏周围脂肪库中的局部旁分泌作用可能在缺血性心脏病的机制中起作用。
