Targeting long non-coding RNA NUDT6 enhances smooth muscle cell survival and limits vascular disease progression.
Targeting long non-coding RNA NUDT6 enhances smooth muscle cell survival and limits vascular disease progression.
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DOI：
10.1016/j.ymthe.2023.04.020
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发表时间：
2023-06-07
影响因子：
12.4
通讯作者：
Maegdefessel, Lars
中科院分区：
文献类型：
--
作者：
Winter, Hanna;Winski, Greg;Busch, Albert;Chernogubova, Ekaterina;Fasolo, Francesca;Wu, Zhiyuan;Baecklund, Alexandra;Khomtchouk, Bohdan B.;Booven, Derek J. Van;Sachs, Nadja;Eckstein, Hans-Henning;Wittig, Ilka;Boon, Reinier A.;Jin, Hong;Maegdefessel, Lars
长链非编码RNA（lncRNA）参与多种生物学过程并调控心血管疾病的发生发展。它们在应对疾病进展方面的潜在治疗益处最近已被广泛探索。我们的研究调查了lncRNA NUDT 6（NUDT 6）及其反义靶向成纤维细胞生长因子2（FGF 2）在两种血管病变中的作用：腹主动脉瘤（AAA）和颈动脉疾病。使用来自两种疾病的组织样本，我们检测到NUDT 6的大幅增加，而FGF 2下调。在颈动脉疾病和AAA的三个鼠和一个猪动物模型中用反义寡核苷酸体内靶向Nudt6限制了疾病进展。Nudt6敲低后FGF 2的恢复改善了血管壁形态和纤维帽稳定性。NUDT 6在体外过表达损害平滑肌细胞（SMC）迁移，同时限制其增殖并增加凋亡。通过采用RNA下拉，然后进行质谱分析以及RNA免疫沉淀，我们鉴定了半胱氨酸和富含甘氨酸的蛋白1（CSRP1）作为另一种直接NUDT 6相互作用伴侣，调节细胞运动性和SMC分化。总体而言，本研究确定NUDT 6作为一个非常保守的FGF2反义转录本。NUDT 6沉默触发SMC存活和迁移，可以作为血管疾病中基于RNA的新治疗策略。
Long non-coding RNAs (lncRNAs) orchestrate various biological processes and regulate the development of cardiovascular diseases. Their potential therapeutic benefit to tackle disease progression has recently been extensively explored. Our study investigates the role of lncRNA Nudix Hydrolase 6 (NUDT6) and its antisense target fibroblast growth factor 2 (FGF2) in two vascular pathologies: abdominal aortic aneurysms (AAA) and carotid artery disease. Using tissue samples from both diseases, we detected a substantial increase of NUDT6, whereas FGF2 was downregulated. Targeting Nudt6 in vivo with antisense oligonucleotides in three murine and one porcine animal model of carotid artery disease and AAA limited disease progression. Restoration of FGF2 upon Nudt6 knockdown improved vessel wall morphology and fibrous cap stability. Overexpression of NUDT6 in vitro impaired smooth muscle cell (SMC) migration, while limiting their proliferation and augmenting apoptosis. By employing RNA pulldown followed by mass spectrometry as well as RNA immunoprecipitation, we identified Cysteine and Glycine Rich Protein 1 (CSRP1) as another direct NUDT6 interaction partner, regulating cell motility and SMC differentiation. Overall, the present study identifies NUDT6 as a well-conserved antisense transcript of FGF2. NUDT6 silencing triggers SMC survival and migration and could serve as a novel RNA-based therapeutic strategy in vascular diseases.
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影响因子：
8
作者：
Busch A;Pauli J;Winski G;Bleichert S;Chernogubova E;Metschl S;Winter H;Trenner M;Wiegering A;Otto C;Fischer J;Reiser J;Werner J;Roy J;Brostjan C;Knappich C;Eckstein HH;Paloschi V;Maegdefessel L
通讯作者：
Maegdefessel L
影响因子：
20.1
作者：
Eken, Suzanne M.;Jin, Hong;Maegdefessel, Lars
通讯作者：
Maegdefessel, Lars
影响因子：
4.3
作者：
Hoshina, K;Koyama, H;Nagawa, H
通讯作者：
Nagawa, H
DOI：
10.1111/j.1749-6632.1999.tb07789.x
发表时间：
1999-01-01
期刊：
THE METABOLIC SYNDROME X
影响因子：
--
作者：
Daugherty, A;Cassis, L
通讯作者：
Cassis, L
影响因子：
--
作者：
Zhang SC;MacDonald KA;Baguma-Nibasheka M;Geldenhuys L;Casson AG;Murphy PR
通讯作者：
Murphy PR