Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH
Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH.
J Am Heart Assoc. 2017 Apr 1;6(4):e004820. doi: 10.1161/JAHA.116.004820.
Numerous epidemiological studies support an inverse association between serum bilirubin levels and the incidence of cardiovascular disease; however, the mechanism(s) by which bilirubin may protect against atherosclerosis is undefined. The goals of the present investigations were to assess the ability of bilirubin to prevent atherosclerotic plaque formation in low-density lipoprotein receptor-deficient ( ) mice and elucidate the molecular processes underlying this effect.
Bilirubin, at physiological concentrations (≤20 μmol/L), dose-dependently inhibits THP-1 monocyte migration across tumor necrosis factor α-activated human umbilical vein endothelial cell monolayers without altering leukocyte binding or cytokine production. A potent antioxidant, bilirubin effectively blocks the generation of cellular reactive oxygen species induced by the cross-linking of endothelial vascular cell adhesion molecule 1 (VCAM-1) or intercellular adhesion molecule 1 (ICAM-1). These findings were validated by treating cells with blocking antibodies or with specific inhibitors of VCAM-1 and ICAM-1 signaling. When administered to mice on a Western diet, bilirubin (30 mg/kg intraperitoneally) prevents atherosclerotic plaque formation, but does not alter circulating cholesterol or chemokine levels. Aortic roots from bilirubin-treated animals exhibit reduced lipid and collagen deposition, decreased infiltration of monocytes and lymphocytes, fewer smooth muscle cells, and diminished levels of chlorotyrosine and nitrotyrosine, without changes in VCAM-1 or ICAM-1 expression.
Bilirubin suppresses atherosclerotic plaque formation in mice by disrupting endothelial VCAM-1- and ICAM-1-mediated leukocyte migration through the scavenging of reactive oxygen species signaling intermediaries. These findings suggest a potential mechanism for the apparent cardioprotective effects of bilirubin.
大量的流行病学研究支持血清胆红素水平与心血管疾病发生率之间呈负相关；然而，胆红素预防动脉粥样硬化的机制尚不清楚。本研究旨在评估胆红素预防载脂蛋白 E 基因敲除（ ）小鼠动脉粥样硬化斑块形成的能力，并阐明其作用的分子机制。
胆红素在生理浓度（≤20μmol/L）下可剂量依赖性地抑制肿瘤坏死因子-α激活的人脐静脉内皮细胞单层中 THP-1 单核细胞的迁移，而不改变白细胞结合或细胞因子的产生。作为一种有效的抗氧化剂，胆红素可有效阻止内皮细胞血管细胞黏附分子 1（VCAM-1）或细胞间黏附分子 1（ICAM-1）交联诱导的细胞活性氧的产生。这些发现通过用阻断抗体或 VCAM-1 和 ICAM-1 信号的特异性抑制剂处理细胞得到了验证。当给 Western 饮食喂养的 小鼠腹腔内注射胆红素（30mg/kg）时，可预防动脉粥样硬化斑块的形成，但不改变循环胆固醇或趋化因子水平。胆红素处理动物的主动脉根部显示脂质和胶原沉积减少，单核细胞和淋巴细胞浸润减少，平滑肌细胞减少，氯酪氨酸和硝基酪氨酸水平降低，而 VCAM-1 或 ICAM-1 的表达没有变化。
胆红素通过清除活性氧信号转导中间产物，抑制载脂蛋白 E 基因敲除（ ）小鼠血管内皮 VCAM-1 和 ICAM-1 介导的白细胞迁移，从而抑制动脉粥样硬化斑块的形成。这些发现提示了胆红素对心脏的保护作用的潜在机制。
