GDF11 prevents the formation of thoracic aortic dissection in mice: Promotion of contractile transition of aortic SMCs.
GDF11 prevents the formation of thoracic aortic dissection in mice: Promotion of contractile transition of aortic SMCs.
复制标题
GDF11预防小鼠胸主动脉夹层的形成：促进主动脉平滑肌细胞的收缩转变
DOI：
10.1111/jcmm.16312
复制
发表时间：
2021-05
影响因子：
5.3
通讯作者：
Yu S
中科院分区：
文献类型：
--
作者：
Ren K;Li B;Liu Z;Xia L;Zhai M;Wei X;Duan W;Yu S
胸主动脉夹层（Thoracic aortic dissection，简称AAA）是一种与细胞外基质成分失调和血管平滑肌细胞（SMC）去分化相关的主动脉疾病。生长分化因子11（GDF11）是与心血管疾病相关的转化生长因子β（TGF-β）超家族成员。本研究旨在探讨GDF11在大鼠主动脉平滑肌细胞中的表达及其对主动脉平滑肌细胞表型转化的影响。GDF 11在升支胸主动脉瘤中的表达低于健康胸主动脉瘤。采用β-氨基丙腈单富马酸酯（BAPN）和血管紧张素II（Ang II）联合应用建立小鼠血管紧张素Ⅱ（Ang Ⅱ）模型。GDF11在腹主动脉组织中的表达也减少，同时伴有炎症、动脉扩张和弹性蛋白降解的增加。给予GDF11减轻了这些主动脉病变，提高了小鼠的存活率。外源性GDF11和腺相关病毒2型（AAV-2）介导的GDF11过表达增加了收缩蛋白ACTA 2、SM22 α和肌球蛋白重链11（MYH 11）的表达，降低了合成标志物骨桥蛋白和纤连蛋白1（FN 1）的表达，表明GDF11可能抑制SMC表型转变并维持其收缩状态。此外，GDF11抑制主动脉SMC中基质金属蛋白酶（MMP）-2，3，9的产生。GDF11增强了典型的TGF-β（Smad2/3）信号传导，而其抑制抑制了GDF11对SMC去分化和MMP产生的抑制作用。因此，我们证明GDF11可能通过抑制炎症和MMP活性，促进主动脉平滑肌细胞向收缩表型转变，从而有助于缓解血管紧张素转换酶，这为血管紧张素转换酶提供了治疗靶点。
Thoracic aortic dissection (TAD) is an aortic disease associated with dysregulated extracellular matrix composition and de‐differentiation of vascular smooth muscle cells (SMCs). Growth Differentiation Factor 11 (GDF11) is a member of transforming growth factor β (TGF‐β) superfamily associated with cardiovascular diseases. The present study attempted to investigate the expression of GDF11 in TAD and its effects on aortic SMC phenotype transition. GDF11 level was found lower in the ascending thoracic aortas of TAD patients than healthy aortas. The mouse model of TAD was established by β‐aminopropionitrile monofumarate (BAPN) combined with angiotensin II (Ang II). The expression of GDF11 was also decreased in thoracic aortic tissues accompanied with increased inflammation, arteriectasis and elastin degradation in TAD mice. Administration of GDF11 mitigated these aortic lesions and improved the survival rate of mice. Exogenous GDF11 and adeno‐associated virus type 2 (AAV‐2)‐mediated GDF11 overexpression increased the expression of contractile proteins including ACTA2, SM22α and myosin heavy chain 11 (MYH11) and decreased synthetic markers including osteopontin and fibronectin 1 (FN1), indicating that GDF11 might inhibit SMC phenotype transition and maintain its contractile state. Moreover, GDF11 inhibited the production of matrix metalloproteinase (MMP)‐2, 3, 9 in aortic SMCs. The canonical TGF‐β (Smad2/3) signalling was enhanced by GDF11, while its inhibition suppressed the inhibitory effects of GDF11 on SMC de‐differentiation and MMP production in vitro. Therefore, we demonstrate that GDF11 may contribute to TAD alleviation via inhibiting inflammation and MMP activity, and promoting the transition of aortic SMCs towards a contractile phenotype, which provides a therapeutic target for TAD.
登录
查看更多内容
DOI：
10.1016/j.bbadis.2019.03.003
发表时间：
2019-06-01
影响因子：
6.2
作者：
Gerardo-Ramirez, Monserrat;Lazzarini-Lechuga, Roberto;Gomez-Quiroz, Luis E.
通讯作者：
Gomez-Quiroz, Luis E.
影响因子：
20.1
作者：
Humphrey JD;Schwartz MA;Tellides G;Milewicz DM
通讯作者：
Milewicz DM
TGFβ 信号的背景
DOI：
10.1038/nrm3434
发表时间：
2012-10
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
37.8
作者：
Evangelista, Arturo;Isselbacher, Eric M.;Eagle, Kim A.
通讯作者：
Eagle, Kim A.
影响因子：
5.5
作者：
Bonafiglia, Quinn A.;Lourenssen, Sandra R.;Blennerhassett, Michael G.
通讯作者：
Blennerhassett, Michael G.