Rac1 mediates cadherin-11 induced cellular pathogenic processes in aortic valve calcification.
Rac1 mediates cadherin-11 induced cellular pathogenic processes in aortic valve calcification.
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DOI：
10.1016/j.carpath.2022.107414
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发表时间：
2022-05
期刊：
影响因子：
--
通讯作者：
Butcher JT
中科院分区：
文献类型：
--
作者：
Vaidya KA;Donnelly MP;Mahmut A;Jang JW;Gee TW;Aibo MI;Bossong R;Hall C;Samb S;Chen J;Butcher JT
钙化性主动脉瓣疾病（CAVD）是外科主动脉瓣置换术的主要原因，目前缺乏可用的药物治疗。钙粘蛋白-11（Cad 11）是一个很有前途的治疗靶点，在体内可促进主动脉瓣钙化，但直接抑制Cad 11在临床试验中一直不成功。相反，靶向下游Cad 11效应子可能在临床上有用;然而，尚未研究介导Cad 11诱导的主动脉瓣细胞发病机制的下游效应子。钙化的人主动脉瓣的免疫荧光显示，GTP-Rac 1在钙化的小叶中高度上调，并且在钙化的瓣膜中与Cad 11的共定位是GTP-RhoA的2.15倍。使用显性负突变体在猪主动脉瓣间质细胞（PAVICs），我们表明，Cad 11主要通过Rac 1调节Runx 2核定位。通过NSC 23766抑制Rac 1-GEF可有效降低用成骨培养基处理的离体猪主动脉瓣叶的钙化2.8倍，还可防止PAVIC中Cad 11诱导的细胞迁移、压实和钙化。GTP-Rac 1和Trio（一种已知的Cad 11结合伴侣和Rac 1-GEF）在心脏瓣膜中条件性过表达Cad 11的Nfatc 1Cre;R26-Cad 11 Tg/Tg（Cad 11 OX）小鼠中分别显著上调3.1倍和6.3倍。最后，我们发现Trio特异性Rac 1-GEF抑制剂ITX 3可有效防止成骨条件下Cad 11诱导的钙化和Runx 2诱导。在这里，我们表明，Cad 11通过Rac 1诱导许多细胞致病过程，Rac 1抑制有效地防止许多Cad 11诱导的主动脉疾病表型。这些发现强调了阻断Rac 1-GEF在CAVD中的治疗潜力。
Calcific aortic valve disease (CAVD), a major cause for surgical aortic valve replacement, currently lacks available pharmacological treatments. Cadherin-11 (Cad11), a promising therapeutic target, promotes aortic valve calcification in vivo, but direct Cad11 inhibition in clinical trials has been unsuccessful. Targeting of downstream Cad11 effectors instead may be clinically useful; however, the downstream effectors that mediate Cad11-induced aortic valve cellular pathogenesis have not been investigated. Immunofluorescence of calcified human aortic valves revealed that GTP-Rac1 is highly upregulated in calcified leaflets and is 2.15 times more co-localized with Cad11 in calcified valves than GTP-RhoA. Using dominant negative mutants in porcine aortic valve interstitial cells (PAVICs), we show that Cad11 predominantly regulates Runx2 nuclear localization via Rac1. Rac1-GEF inhibition via NSC23766 effectively reduces calcification in ex vivo porcine aortic valve leaflets treated with osteogenic media by 2.8-fold and also prevents Cad11-induced cell migration, compaction, and calcification in PAVICs. GTP-Rac1 and Trio, a known Cad11 binding partner and Rac1-GEF, are significantly upregulated in Nfatc1Cre;R26-Cad11Tg/Tg (Cad11 OX) mice that conditionally overexpress Cad11 in the heart valves by 3.1-fold and 6.3-fold, respectively. Finally, we found that the Trio-specific Rac1-GEF inhibitor, ITX3, effectively prevents Cad11-induced calcification and Runx2 induction in osteogenic conditions. Here we show that Cad11 induces many cellular pathogenic processes via Rac1 and that Rac1 inhibition effectively prevents many Cad11-induced aortic disease phenotypes. These findings highlight the therapeutic potential of blocking Rac1-GEFs in CAVD.
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影响因子：
4.9
作者：
Abreu, Joana R. F.;Dontje, Wendy;Tak, Paul P.
通讯作者：
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影响因子：
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作者：
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通讯作者：
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DOI：
10.1083/jcb.201604015
发表时间：
2016-11-21
期刊：
The Journal of cell biology
影响因子：
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通讯作者：
Butcher, Jonathan T.
DOI：
10.1073/pnas.1019437108
发表时间：
2011-05-17
影响因子：
11.1
作者：
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通讯作者：
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