Abnormal extracellular matrix protein transport associated with increased apoptosis of vascular smooth muscle cells in Marfan syndrome and bicuspid aortic valve thoracic aortic aneurysm
Abnormal extracellular matrix protein transport associated with increased apoptosis of vascular smooth muscle cells in Marfan syndrome and bicuspid aortic valve thoracic aortic aneurysm
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DOI：
10.1161/01.cir.0000087660.82721.15
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发表时间：
2003-09-09
期刊：
影响因子：
37.8
通讯作者：
Watanabe, T
中科院分区：
文献类型：
--
作者：
Nataatmadja, M;West, M;Watanabe, T
背景 - 马凡综合征 (MS) 是一种由原纤维蛋白基因 FBN1 突变引起的遗传性疾病。二叶式主动脉瓣（BAV）是一种原因不明的先天性心脏畸形。这两种情况都与升主动脉瘤和过早死亡有关。本研究探讨了细胞外基质蛋白原纤维蛋白、纤连蛋白、腱蛋白的分泌与血管平滑肌细胞 (VSMC) 凋亡之间的关系。研究了基质金属蛋白酶 (MMP)-2 在 MS 动脉瘤中 VSMC 凋亡中的作用。方法和结果 - 动脉瘤组织取自接受手术的患者（MS：4 M、1 F，年龄 27 - 45 岁；BAV：3 M、2 F，年龄 28 - 65 岁）。还收集了非动脉瘤疾病受试者的正常主动脉（4 M，1 F，年龄 23 - 93 岁）。 MS 和 BAV 动脉瘤组织学显示囊性内侧坏死 (CMN) 区域，无炎症浸润。对培养的 MS 和 BAV VSMC 的免疫组织化学研究表明，原纤维蛋白、纤连蛋白和腱蛋白在细胞内积累，细胞外分布减少。蛋白质印迹显示 MS 或 BAV VSMC 中原纤维蛋白、纤连蛋白或生腱蛋白的表达没有增加，而 MS VSMC 中 MMP-2 的表达增加。与对照 (7 +/- 5%) 相比，MS (27 +/- 8%) 和 BAV (32 +/- 14%) 中培养的 VSMC 在无血清培养基中孵育 24 小时的损失增加了 4 倍。结论 - 在 MS 和 BAV 中，分泌蛋白的数量和质量均发生变化，VSMC 凋亡程度增加。 MMP-2 的上调可能在 MS VSMC 中的 VSMC 凋亡中发挥作用。研究结果表明，BAV 胸主动脉存在基本细胞异常，可能是遗传原因。
Background - Marfan syndrome (MS) is a genetic disorder caused by a mutation in the fibrillin gene FBN1. Bicuspid aortic valve (BAV) is a congenital heart malformation of unknown cause. Both conditions are associated with ascending aortic aneurysm and premature death. This study examined the relationship among the secretion of extracellular matrix proteins fibrillin, fibronectin, tenascin, and vascular smooth muscle cell (VSMC) apoptosis. The role of matrix metalloproteinase (MMP)- 2 in VSMC apoptosis was studied in MS aneurysm.Methods and Results - Aneurysm tissue was obtained from patients undergoing surgery ( MS: 4 M, 1 F, age 27 - 45 years; BAV: 3 M, 2 F, age 28 - 65 years). Normal aorta from subjects with nonaneurysm disease was also collected ( 4 M, 1 F, age 23 - 93 years). MS and BAV aneurysm histology showed areas of cystic medial necrosis (CMN) without inflammatory infiltrate. Immunohistochemical study of cultured MS and BAV VSMC showed intracellular accumulation and reduction of extracellular distribution of fibrillin, fibronectin, and tenascin. Western blot showed no increase in expression of fibrillin, fibronectin, or tenascin in MS or BAV VSMC and increased expression of MMP-2 in MS VSMCs. There was 4-fold increase in loss of cultured VSMC incubated in serum-free medium for 24 hours in both MS ( 27 +/- 8%) and BAV ( 32 +/- 14%) compared with control ( 7 +/- 5%).Conclusions - In MS and BAV there is alteration in both the amount and quality of secreted proteins and an increased degree of VSMC apoptosis. Up-regulation of MMP-2 might play a role in VSMC apoptosis in MS VSMC. The findings suggest the presence of a fundamental cellular abnormality in BAV thoracic aorta, possibly of genetic origin.