Ciclopirox Inhibition of eIF5A Hypusination Attenuates Fibroblast Activation and Cardiac Fibrosis.
Ciclopirox Inhibition of eIF5A Hypusination Attenuates Fibroblast Activation and Cardiac Fibrosis.
复制标题
环吡酮抑制eIF5A高嘌呤化减弱成纤维细胞活化和心脏纤维化。
DOI：
10.3390/jcdd10020052
复制
发表时间：
2023-01-29
影响因子：
2.4
通讯作者：
中科院分区：
文献类型：
--
作者：
心脏纤维化是心力衰竭（HF）的主要原因，被认为是心力衰竭治疗的一个有针对性的过程。心脏成纤维细胞（CF）的激活伴随着细胞外基质（ECM）的过量产生，对于心脏纤维化中纤维化疤痕的启动和维持至关重要。然而，靶向 CF 激活的治疗化合物在治疗心脏纤维化方面仍然有限。真核翻译起始因子 5A (eIF5A) 在被羟丁化后对于富含脯氨酸密码子的 mRNA 的翻译延伸至关重要。在这项研究中，我们发现，在心肌梗塞 (MI) 小鼠模型中，hypuslated eIF5A 蛋白水平升高与心脏纤维化和心功能障碍相关。环吡酮 (CPX) 是一种 FDA 批准的抗真菌药物，可抑制 eIF5A 催眠所需的脱氧马尿碱羟化酶 (DOHH)。预防性和逆转小鼠模型的结果表明，CPX 治疗显着减少 MI 驱动的心脏纤维化并改善心脏功能。对分离的小鼠原发性 CF 的体外研究表明，使用 CPX 抑制 eIF5A 抑制可显着消除 TGFβ 诱导的 CF 增殖、活化和胶原蛋白表达。小鼠 CF 的蛋白质组学分析表明，CPX 下调富含脯氨酸的蛋白质的表达，这些蛋白质富含细胞外基质和细胞粘附途径。我们的研究结果与人类心脏病相关，因为与健康受试者相比，在缺血性心力衰竭患者的心脏样本中观察到了hypuslated eIF5A水平升高。总之，这些结果表明 CPX 可以重新用于治疗心脏纤维化和缺血性心力衰竭。
Cardiac fibrosis is a primary contributor to heart failure (HF), and is considered to be a targetable process for HF therapy. Cardiac fibroblast (CF) activation accompanied by excessive extracellular matrix (ECM) production is central to the initiation and maintenance of fibrotic scarring in cardiac fibrosis. However, therapeutic compounds targeting CF activation remain limited in treating cardiac fibrosis. Eukaryotic translation initiation factor 5A (eIF5A), upon being hypusinated, is essential for the translation elongation of proline-codon rich mRNAs. In this study, we found that increased hypusinated eIF5A protein levels were associated with cardiac fibrosis and heart dysfunction in myocardial infarction (MI) mouse models. Ciclopirox (CPX), an FDA-approved antifungal drug, inhibits the deoxyhypusine hydroxylase (DOHH) enzyme required for eIF5A hypusination. Results from preventive and reversal mouse models suggest that CPX treatment significantly reduced MI-driven cardiac fibrosis and improved cardiac function. In vitro studies of isolated mouse primary CFs revealed that inhibition of eIF5A hypusination using CPX significantly abolished TGFβ induced CF proliferation, activation, and collagen expression. Proteomic analysis from mouse CFs reveals that CPX downregulates the expression of proline-rich proteins that are enriched in extracellular matrix and cell adhesion pathways. Our findings are relevant to human heart disease, as increased hypusinated eIF5A levels were observed in heart samples of ischemic heart failure patients compared to healthy subjects. Together, these results suggest that CPX can be repurposed to treat cardiac fibrosis and ischemic heart failure.
登录
查看更多内容
影响因子：
20.1
作者：
Wu, Jiangbin;Subbaiah, Kadiam C. Venkata;Yao, Peng
通讯作者：
Yao, Peng
影响因子：
16
作者：
Zhang, Hanlin;Alsaleh, Ghada;Simon, Anna Katharina
通讯作者：
Simon, Anna Katharina
影响因子：
5.9
作者：
通讯作者：
--
影响因子：
5.4
作者：
Qin P;Arabacilar P;Bernard RE;Bao W;Olzinski AR;Guo Y;Lal H;Eisennagel SH;Platchek MC;Xie W;Del Rosario J;Nayal M;Lu Q;Roethke T;Schnackenberg CG;Wright F;Quaile MP;Halsey WS;Hughes AM;Sathe GM;Livi GP;Kirkpatrick RB;Qu XA;Rajpal DK;Faelth Savitski M;Bantscheff M;Joberty G;Bergamini G;Force TL;Gatto GJ Jr;Hu E;Willette RN
通讯作者：
Willette RN
影响因子：
3.6
作者：
Gupta, AK;Skinner, AR
通讯作者：
Skinner, AR