LncRNA Airn alleviates diabetic cardiac fibrosis by inhibiting activation of cardiac fibroblasts via a m6A-IMP2-p53 axis.
LncRNA Airn alleviates diabetic cardiac fibrosis by inhibiting activation of cardiac fibroblasts via a m6A-IMP2-p53 axis.
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DOI：
10.1186/s13062-022-00346-6
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发表时间：
2022-11-16
期刊：
影响因子：
5.5
通讯作者：
中科院分区：
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心脏纤维化是糖尿病患者心功能不全的主要原因。然而，心脏纤维化的潜在机制仍不清楚。本研究旨在探讨长链非编码RNA（LncRNA）Airn在糖尿病心肌病（DCM）心肌纤维化发病机制中的作用。用链脲佐菌素诱发小鼠糖尿病。使用心肌内腺相关病毒（AAV）来操纵Airn表达。在体外和体内研究DCM纤维化的功能意义和潜在机制。糖尿病心脏表现出明显的心功能损害，并伴有明显的心脏纤维化。有趣的是，lncRNA Airn表达在糖尿病心脏和高葡萄糖（HG）处理的心脏成纤维细胞（CF）中均显著降低。腺相关病毒介导的Airn重建可预防心脏纤维化和扩张型心肌病的发生，而Airn敲除可诱导心脏纤维化表型扩张型心肌病。在体外，Airn逆转了HG诱导的成纤维细胞-肌成纤维细胞转化、CFs异常增殖和I型胶原的断裂。相反，Airn敲低模拟HG诱导的CFs表型。从机制上讲，我们发现Airn通过直接结合胰岛素样生长因子2 mRNA结合蛋白2（IMP 2）发挥抗纤维化作用，并进一步阻止其泛素化依赖性降解。此外，我们发现Airn/IMP 2以m6 A方式保护p53 mRNA免于降解，导致CF细胞周期停滞和减少心脏纤维化。因此，消融p53减弱了Airn对成纤维细胞活化和心脏纤维化的抑制作用。我们的研究首次证明，Airn以m6 A依赖的方式通过IMP 2-p53轴预防糖尿病心脏中心脏纤维化的发展。LncRNA Airn可能是DCM心脏纤维化的一个有前途的治疗靶点。在线版本包含补充材料，可通过10.1186/s13062-022-00346-6获得。
Cardiac fibrosis is a leading cause of cardiac dysfunction in patients with diabetes. However, the underlying mechanisms of cardiac fibrosis remain unclear. This study aimed to investigate the role of the long non-coding RNA (LncRNA) Airn in the pathogenesis of cardiac fibrosis in diabetic cardiomyopathy (DCM) and its underlying mechanism. Diabetes mellitus (DM) was induced in mice by streptozotocin injection. An intramyocardial adeno-associated virus (AAV) was used to manipulate Airn expression. The functional significance and underlying mechanisms in DCM fibrosis were investigated both in vitro and in vivo. Diabetic hearts showed a significant impairment in cardiac function, accompanied by obviously increased cardiac fibrosis. Interestingly, lncRNA Airn expression was significantly decreased in both diabetic hearts and high glucose (HG)-treated cardiac fibroblasts (CFs). AAV-mediated Airn reconstitution prevented cardiac fibrosis and the development of DCM, while Airn knockdown induced cardiac fibrosis phenotyping DCM. As in vitro, Airn reversed HG-induced fibroblast-myofibroblast transition, aberrant CFs proliferation and section of collagen I. In contrast, Airn knockdown mimicked a HG-induced CFs phenotype. Mechanistically, we identified that Airn exerts anti-fibrotic effects by directly binding to insulin-like growth factor 2 mRNA-binding protein 2 (IMP2) and further prevents its ubiquitination-dependent degradation. Moreover, we revealed that Airn/IMP2 protected p53 mRNA from degradation in m6A manner, leading to CF cell cycle arrest and reduced cardiac fibrosis. As a result, ablation of p53 blunted the inhibitory effects of Airn on fibroblast activation and cardiac fibrosis. Our study demonstrated for the first time that Airn prevented the development of cardiac fibrosis in diabetic heart via IMP2-p53 axis in an m6A dependent manner. LncRNA Airn could be a promising therapeutic target for cardiac fibrosis in DCM. The online version contains supplementary material available at 10.1186/s13062-022-00346-6.
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DOI：
10.1016/j.trsl.2014.05.001
发表时间：
2014-10
期刊：
Translational research : the journal of laboratory and clinical medicine
影响因子：
--
作者：
Cavalera M;Wang J;Frangogiannis NG
通讯作者：
Frangogiannis NG
TNAP 抑制通过停用 TGF-β1/Smads 和激活 P53 信号通路来减轻心肌梗塞引起的心脏纤维化。
影响因子：
9
作者：
Gao, Lei;Wang, Li-you;Zhang, Dong-ying
通讯作者：
Zhang, Dong-ying
影响因子：
3.9
作者：
Marcho C;Bevilacqua A;Tremblay KD;Mager J
通讯作者：
Mager J
影响因子：
6.7
作者：
Cai, Huajie;Zheng, Yihu;Zhang, Qiyu
通讯作者：
Zhang, Qiyu
影响因子：
5.5
作者：
Ju W;Liu K;Ouyang S;Liu Z;He F;Wu J
通讯作者：
Wu J