Noncanonical TGFβ signaling contributes to aortic aneurysm progression in Marfan syndrome mice.
Noncanonical TGFβ signaling contributes to aortic aneurysm progression in Marfan syndrome mice.
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DOI：
10.1126/science.1192149
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发表时间：
2011-04-15
期刊：
影响因子：
--
通讯作者：
Dietz HC
中科院分区：
文献类型：
--
作者：
Holm TM;Habashi JP;Doyle JJ;Bedja D;Chen Y;van Erp C;Lindsay ME;Kim D;Schoenhoff F;Cohn RD;Loeys BL;Thomas CJ;Patnaik S;Marugan JJ;Judge DP;Dietz HC
转化生长因子-β(转化生长因子-β)信号通路在包括马凡综合征(MFS)在内的多种疾病中推动动脉瘤的进展，抑制该信号转导通路的治疗正在进行临床试验。转化生长因子β可以刺激多种细胞内信号通路，但目前尚不清楚这些通路中的哪一条会导致主动脉疾病，当被抑制时，哪一条会导致疾病的改善。在这里，我们显示细胞外信号调节激酶1和2和Smad2在MFS的小鼠模型中被激活，并且两者都被针对转化生长因子β的治疗所抑制。选择性抑制ERK1/2的激活可以改善MFS小鼠的主动脉生长，而Smad4缺乏则会加重MFS小鼠的主动脉疾病并导致过早死亡。Smad4基因缺陷的MFS小鼠独特地表现出Jun N末端激酶-1(JNK1)的激活，JNK拮抗剂改善了Smad4完全表达缺失或保留的MFS小鼠的主动脉生长。因此，非规范(Smad非依赖性)转化生长因子β信号是MFS小鼠主动脉疾病的重要驱动因素，抑制ERK1/2或JNK1通路是治疗该疾病的潜在策略。
Transforming growth factor–β (TGFβ) signaling drives aneurysm progression in multiple disorders, including Marfan syndrome (MFS), and therapies that inhibit this signaling cascade are in clinical trials. TGFβ can stimulate multiple intracellular signaling pathways, but it is unclear which of these pathways drives aortic disease and, when inhibited, which result in disease amelioration. Here we show that extracellular signal–regulated kinase (ERK) 1 and 2 and Smad2 are activated in a mouse model of MFS, and both are inhibited by therapies directed against TGFβ. Whereas selective inhibition of ERK1/2 activation ameliorated aortic growth, Smad4 deficiency exacerbated aortic disease and caused premature death in MFS mice. Smad4-deficient MFS mice uniquely showed activation of Jun N-terminal kinase–1 (JNK1), and a JNK antagonist ameliorated aortic growth in MFS mice that lacked or retained full Smad4 expression. Thus, noncanonical (Smad-independent) TGFβ signaling is a prominent driver of aortic disease in MFS mice, and inhibition of the ERK1/2 or JNK1 pathways is a potential therapeutic strategy for the disease.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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作者：
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DOI：
10.1152/ajprenal.00139.2003
发表时间：
2004-02-01
影响因子：
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作者：
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