Division of Cardiology, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
These authors contributed equally: Mahmoud Salama Ahmed, Ngoc Uyen Nhi Nguyen.
Nat Cardiovasc Res. 2024 Mar;3(3):372-388. doi: 10.1038/s44161-024-00450-y. Epub 2024 Mar 11.
Targeting Meis1 and Hoxb13 transcriptional activity could be a viable therapeutic strategy for heart regeneration. In this study, we performd an in silico screening to identify FDA-approved drugs that can inhibit Meis1 and Hoxb13 transcriptional activity based on the resolved crystal structure of Meis1 and Hoxb13 bound to DNA. Paromomycin (Paro) and neomycin (Neo) induced proliferation of neonatal rat ventricular myocytes in vitro and displayed dose-dependent inhibition of Meis1 and Hoxb13 transcriptional activity by luciferase assay and disruption of DNA binding by electromobility shift assay. X-ray crystal structure revealed that both Paro and Neo bind to Meis1 near the Hoxb13-interacting domain. Administration of Paro-Neo combination in adult mice and in pigs after cardiac ischemia/reperfusion injury induced cardiomyocyte proliferation, improved left ventricular systolic function and decreased scar formation. Collectively, we identified FDA-approved drugs with therapeutic potential for induction of heart regeneration in mammals.
靶向 Meis1 和 Hoxb13 的转录活性可能是心脏再生的一种可行的治疗策略。在这项研究中，我们进行了计算机筛选，以确定基于已解决的 Meis1 和 Hoxb13 与 DNA 结合的晶体结构，哪些 FDA 批准的药物可以抑制 Meis1 和 Hoxb13 的转录活性。新霉素（Paro）和正定霉素（Neo）在体外诱导新生大鼠心室肌细胞增殖，并通过荧光素酶测定和电泳迁移率变动分析显示出剂量依赖性抑制 Meis1 和 Hoxb13 的转录活性。X 射线晶体结构表明，Paro 和 Neo 都结合在 Meis1 靠近 Hoxb13 相互作用域的部位。在成年小鼠和心脏缺血/再灌注损伤后的猪中给予 Paro-Neo 联合治疗，可诱导心肌细胞增殖，改善左心室收缩功能，减少瘢痕形成。总之，我们鉴定出了具有在哺乳动物中诱导心脏再生治疗潜力的 FDA 批准药物。
