Bilirubin inhibits neointima formation and vascular smooth muscle cell proliferation and migration.
Bilirubin inhibits neointima formation and vascular smooth muscle cell proliferation and migration.
复制标题
DOI：
10.3389/fphar.2012.00048
复制
发表时间：
2012
影响因子：
5.6
通讯作者：
Durante W
中科院分区：
文献类型：
--
作者：
Peyton KJ;Shebib AR;Azam MA;Liu XM;Tulis DA;Durante W
胆红素是由血红素加氧酶和胆绿素还原酶协同作用产生的一种血红素代谢物。虽然长期以来被认为是血红素分解代谢的有毒副产品，但最近的临床前和临床研究表明，胆红素在循环中发挥有益的作用。在目前的研究中，我们确定了局部给予胆红素是否减少了大鼠颈动脉损伤后的新生内膜形成。此外，还研究了胆红素对人动脉平滑肌细胞(SMCs)增殖和迁移的调节作用。大鼠颈动脉球囊损伤后立即给予血管周围局部胆红素可显著减少新生内膜的形成。胆红素抑制新生内膜增厚与损伤血管ERK活性、细胞周期蛋白D1和A蛋白表达显著降低、p21和P53蛋白表达增加有关。胆红素以浓度依赖的方式抑制人主动脉SMCs的增殖和迁移，而不影响细胞的存活。此外，胆红素使细胞周期中处于G0/G1期的细胞比例呈浓度依赖性增加，而处于S和G2M期的细胞比例下降。胆红素对血管内皮细胞线粒体功能和ATP含量无明显影响。总之，这些研究表明，胆红素抑制动脉损伤后新生内膜的形成，这与细胞周期调节蛋白的表达变化有关。此外，胆红素还能阻止人动脉系膜细胞的增殖和迁移，并使系膜细胞停滞在细胞周期的G0/G1期。胆红素是治疗闭塞性血管疾病的一种有吸引力的治疗药物。
Bilirubin is a heme metabolite generated by the concerted action of the enzymes heme oxygenase and biliverdin reductase. Although long considered a toxic byproduct of heme catabolism, recent preclinical, and clinical studies indicate the bilirubin exerts beneficial effects in the circulation. In the present study, we determined whether local administration of bilirubin attenuates neointima formation following injury of rat carotid arteries. In addition, the ability of bilirubin to regulate the proliferation and migration of human arterial smooth muscle cells (SMCs) was investigated. Local perivascular administration of bilirubin immediately following balloon injury of rat carotid arteries significantly attenuated neointima formation. Bilirubin-mediated inhibition of neointimal thickening was associated with a significant decrease in ERK activity and cyclin D1 and A protein expression, and an increase in p21 and p53 protein expression in injured blood vessels. Treatment of human aortic SMCs with bilirubin inhibited proliferation and migration in a concentration-dependent manner without affecting cell viability. In addition, bilirubin resulted in a concentration-dependent increase in the percentage of cells in the G0/G1 phase of the cell cycle and this was paralleled by a decrease in the fraction of cells in the S and G2M phases of the cell cycle. Finally, bilirubin had no effect on mitochondrial function and ATP content of vascular SMCs. In conclusion, these studies demonstrate that bilirubin inhibits neointima formation after arterial injury and this is associated with alterations in the expression of cell cycle regulatory proteins. Furthermore, bilirubin blocks proliferation and migration of human arterial SMCs and arrests SMCs in the G0/G1 phase of the cell cycle. Bilirubin represents an attractive therapeutic agent in treating occlusive vascular disease.
登录
查看更多内容
影响因子：
4.3
作者：
Oellinger, Robert;Kogler, Pamela;Margreiter, Raimund
通讯作者：
Margreiter, Raimund
影响因子：
37.8
作者：
Nakao, A;Murase, N;Kanno, S
通讯作者：
Kanno, S
DOI：
10.1152/ajpcell.2000.279.4.c999
发表时间：
2000-10-01
影响因子：
5.5
作者：
Fukui, R;Amakawa, M;Ohsawa, N
通讯作者：
Ohsawa, N
DOI：
10.1161/01.atv.0000184779.01822.9d
发表时间：
2005-11-01
影响因子：
8.7
作者：
Granada, JF;Ensenat, D;Durante, W
通讯作者：
Durante, W
DOI：
10.1161/atvbaha.107.153262
发表时间：
2008-01-01
影响因子：
8.7
作者：
Perlstein, Todd S.;Pande, Reena L.;Creager, Mark A.
通讯作者：
Creager, Mark A.