High serum thrombospondin-1 concentration is associated with slower abdominal aortic aneurysm growth and deficiency of thrombospondin-1 promotes angiotensin II induced aortic aneurysm in mice
High serum thrombospondin-1 concentration is associated with slower abdominal aortic aneurysm growth and deficiency of thrombospondin-1 promotes angiotensin II induced aortic aneurysm in mice
复制标题
高血清血小板反应蛋白-1浓度与腹主动脉瘤生长缓慢相关，血小板反应蛋白-1缺乏促进血管紧张素II诱导的小鼠主动脉瘤
DOI：
10.1042/cs20160970
复制
发表时间：
2017-06-01
期刊：
影响因子：
6
通讯作者：
Golledge, Jonathan
中科院分区：
文献类型：
--
作者：
Krishna, Smriti Murali;Seto, Sai Wang;Golledge, Jonathan
腹主动脉瘤（AAA）是一种常见的年龄相关性血管疾病，其特征是主动脉壁进行性弱化和扩张。血小板反应蛋白-1（TSP-1;基因Thbs 1）是在控制细胞外基质（ECM）重塑中重要的基质细胞蛋白家族的成员。在本研究中，对276名接受重复超声检查的男性进行了评估，评估了血清TSP-1浓度与AAA进展的相关性，平均时间为5.5年。AAA生长与血清TSP-1浓度呈负相关（斯皮尔曼rho-0.129，P=0.033）。TSP-1在最高四分位数的男性在随访期间AAA生长的可能性降低大于中位数（OR：0.40; 95%置信区间（CI）：0.19-0.84，P=0.016，根据其他风险因素调整）。与相对正常的AAA瘤颈相比，TSP-1的免疫组织化学染色在AAA体组织中减少。为了进一步评估TSP-1在AAA起始和进展中的作用，将TSP-1和载脂蛋白缺陷型小鼠（Thbs 1（-/-）ApoE（-/-），n= 20）和对照小鼠（ApoE（-/-），n= 20）用血管紧张素II（AngII）皮下输注28天。AngII输注后，Thbs 1（-/-）ApoE（-/-）小鼠通过超声（P=0.024）和离体形态测量（P=0.006）具有更大的AAA。Thbs 1（-/-）ApoE（-/-）小鼠还显示弹性蛋白丝降解增加，沿着全身水平和基质金属蛋白酶（MMP）-9的主动脉表达升高。从Thbs 1（-/-）ApoE（-/-）小鼠分离的肾上主动脉节段和血管平滑肌细胞（VSMC）显示胶原3A 1基因表达降低。此外，Thbs 1（-/-）ApoE（-/-）小鼠的主动脉低密度脂蛋白（LDL）受体相关蛋白1的表达减少。总的来说，本研究的结果表明，TSP-1缺乏促进ECM的适应不良重塑，导致AAA进展加速。
Abdominal aortic aneurysm (AAA) is a common age-related vascular disease characterized by progressive weakening and dilatation of the aortic wall. Thrombospondin-1 (TSP-1; gene Thbs1) is a member of the matricellular protein family important in the control of extracellular matrix (ECM) remodelling. In the present study, the association of serum TSP-1 concentration with AAA progression was assessed in 276 men that underwent repeated ultrasound for a median 5.5 years. AAA growth was negatively correlated with serum TSP-1 concentration (Spearman's rho -0.129, P=0.033). Men with TSP-1 in the highest quartile had a reduced likelihood of AAA growth greater than median during follow-up (OR: 0.40; 95% confidence interval (CI): 0.19-0.84, P=0.016, adjusted for other risk factors). Immunohistochemical staining for TSP-1 was reduced in AAA body tissues compared with the relatively normal AAA neck. To further assess the role of TSP-1 in AAA initiation and progression, combined TSP-1 and apolipoprotein deficient (Thbs1(-/-) ApoE(-/-), n= 20) and control mice (ApoE(-/-), n= 20) were infused subcutaneously with angiotensin II (AngII) for 28 days. Following AngII infusion, Thbs1(-/-)ApoE(-/-)mice had larger AAAs by ultrasound (P=0.024) and ex vivo morphometry measurement (P=0.006). The Thbs1(-/-) ApoE(-/-) mice also showed increased elastin filament degradation along with elevated systemic levels and aortic expression of matrix metalloproteinase (MMP)-9. Suprarenal aortic segments and vascular smooth muscle cells (VSMCs) isolated from Thbs1(-/-) ApoE(-/-) mice showed reduced collagen 3A1 gene expression. Furthermore, Thbs1(-/-) ApoE(-/-) mice had reduced aortic expression of low-density lipoprotein (LDL) receptor-related protein 1. Collectively, findings from the present study suggest that TSP-1 deficiency promotes maladaptive remodelling of the ECM leading to accelerated AAA progression.