Institute of Molecular Cardiology, Division of Cardiovascular Medicine, Department of Medicine, University of Louisville, Louisville, Kentucky, USA.
Department of Cardiovascular Medicine, Faculty of Medicine, Zagazig University, Zagazig, Egypt.
Br J Pharmacol. 2023 Dec;180(24):3271-3289. doi: 10.1111/bph.16209. Epub 2023 Aug 30.
Myocardial infarction (MI) is the leading cause of mortality globally due in part to the limited ability of cardiomyocytes (CMs) to regenerate. Recently, we demonstrated that overexpression of four-cell cycle factors, CDK1, CDK4, cyclin B1 and cyclin D1 (4F), induced cell division in ~20% of the post-mitotic CMs overexpressed 4F. The current study aims to identify a small molecule that augments 4F-induced CM cycle induction.
EXPERIMENTAL APPROACH, KEY RESULTS: Screening of small molecules with a potential to augment 4F-induced cell-cycle induction in 60-day-old mature human induced pluripotent cardiomyocytes (hiPS-CMs) revealed N-(4,6-Dimethylpyridin-2-yl)-4-(pyridine-4-yl)piperazine-1-carbothioamide (NDPPC), which activates cell cycle progression in 4F-transduced hiPS-CMs. Autodock tool and Autodock vina computational methods showed that NDPPC has a potential interaction with the binding site at the human p38⍺ mitogen-activated protein kinase (p38⍺ MAP kinase), a critical negative regulator of the mammalian cell cycle. A p38 MAP kinase activity assay showed that NDPPC inhibits p38⍺ with 5-10 times lower IC compared to the other P38 isoforms in a dose-dependent manner. Overexpression of p38⍺ MAP kinase in CMs inhibited 4F cell cycle induction, and treatment with NDPPC reversed the cell cycle inhibitory effect.
NDPPC is a novel inhibitor for p38 MAP kinase and is a promising drug to augment CM cell cycle response to the 4F. NDPPC could become an adjunct treatment with other cell cycle activators for heart failure treatment.
心肌梗死（MI）是全球范围内导致死亡的主要原因，部分原因是心肌细胞（CMs）的再生能力有限。最近，我们证明了过度表达细胞周期因子 CDK1、CDK4、细胞周期蛋白 B1 和细胞周期蛋白 D1（4F）可使约 20%的表达 4F 的有丝分裂后 CMs 发生细胞分裂。本研究旨在鉴定一种可增强 4F 诱导的 CM 周期诱导的小分子。
实验方法，主要结果：筛选了一种具有增强 4F 诱导的 60 日龄成熟人诱导多能心肌细胞（hiPS-CMs）中细胞周期诱导潜能的小分子，发现 N-(4,6-二甲基吡啶-2-基）-4-(吡啶-4-基)哌嗪-1-甲脒（NDPPC）可激活 4F 转导的 hiPS-CMs 中的细胞周期进程。Autodock 工具和 Autodock vina 计算方法表明，NDPPC 与人 p38 ⍺ 有丝分裂原激活蛋白激酶（p38 ⍺ MAP kinase）的结合位点具有潜在相互作用，p38 ⍺ MAP kinase 是哺乳动物细胞周期的关键负调控因子。p38 ⍺ MAP 激酶活性测定表明，NDPPC 以剂量依赖性方式以比其他 P38 同工型低 5-10 倍的 IC 抑制 p38 ⍺。CMs 中 p38 ⍺ MAP 激酶的过表达抑制了 4F 细胞周期诱导，而 NDPPC 处理逆转了细胞周期抑制作用。
NDPPC 是一种新型的 p38 MAP 激酶抑制剂，是增强 4F 对 CM 细胞周期反应的有前途的药物。NDPPC 可能成为其他细胞周期激活剂治疗心力衰竭的辅助治疗方法。
