北京大学Lu Tie等研究人员合作发现，抑制ROCK1可通过RIPK4/AMPK通路改善糖尿病患者的伤口愈合。该研究于2024年3月27日在线发表于国学术期刊《中国药理学报》。

研究人员探讨了Rho相关蛋白激酶-1（ROCK1）在糖尿病伤口愈合中的作用及分子机制。结果显示，ROCK1在糖尿病患者、链脲佐菌素（STZ）诱导的糖尿病小鼠和db/db糖尿病小鼠伤口肉芽组织中的表达明显增加。ROCK1抑制剂法舒地尔对糖尿病小鼠伤口愈合和血液灌注有剂量依赖性改善作用。在内皮细胞中，法舒地尔和ROCK1 siRNA能显著提高单磷酸腺苷激活的蛋白激酶，在Thr172处的磷酸化（pThr¹⁷²-AMPKα）和内皮一氧化氮合酶（eNOS）的活性，并抑制线粒体活性氧（mtROS）和硝基酪氨酸的形成。

综合生物信息学分析和共沉淀实验证实，ROCK1通过与受体相互作用丝氨酸/苏氨酸激酶4（RIPK4）结合，抑制了pThr¹⁷²-AMPKα。这些结果表明，法舒地尔至少部分通过ROCK1/RIPK4/AMPK途径加速伤口修复和改善血管生成。法舒地尔可能是糖尿病患者难治性伤口的一种潜在治疗方法。

据了解，难治性伤口是糖尿病的一种严重并发症，由于缺乏有效的治疗方法和治疗靶点，往往会导致截肢。难治性伤口的发病机制十分复杂，涉及多种类型的细胞。ROCK1磷酸化一系列底物，触发下游信号通路，影响多种细胞过程，包括细胞迁移、通讯和增殖。

附：英文原文

Title: ROCK1 inhibition improves wound healing in diabetes via RIPK4/AMPK pathway

Author: Huyan, Tianru, Fan, Lu, Zheng, Zhong-yuan, Zhao, Jing-hui, Han, Zhen-ru, Wu, Pin, Ma, Qun, Du, Ya-qin, Shi, Yun-di, Gu, Chun-yan, Li, Xue-jun, Wang, Wen-hui, Zhang, Long, Tie, Lu

Issue&Volume: 2024-03-27

Abstract: Refractory wounds are a severe complication of diabetes mellitus that often leads to amputation because of the lack of effective treatments and therapeutic targets. The pathogenesis of refractory wounds is complex, involving many types of cells. Rho-associated protein kinase-1 (ROCK1) phosphorylates a series of substrates that trigger downstream signaling pathways, affecting multiple cellular processes, including cell migration, communication, and proliferation. The present study investigated the role of ROCK1 in diabetic wound healing and molecular mechanisms. Our results showed that ROCK1 expression significantly increased in wound granulation tissues in diabetic patients, streptozotocin (STZ)-induced diabetic mice, and db/db diabetic mice. Wound healing and blood perfusion were dose-dependently improved by the ROCK1 inhibitor fasudil in diabetic mice. In endothelial cells, fasudil and ROCK1 siRNA significantly elevated the phosphorylation of adenosine monophosphate-activated protein kinase at Thr172 (pThr172-AMPKα), the activity of endothelial nitric oxide synthase (eNOS), and suppressed the levels of mitochondrial reactive oxygen species (mtROS) and nitrotyrosine formation. Experiments using integrated bioinformatics analysis and coimmunoprecipitation established that ROCK1 inhibited pThr172-AMPKα by binding to receptor-interacting serine/threonine kinase 4 (RIPK4). These results suggest that fasudil accelerated wound repair and improved angiogenesis at least partially through the ROCK1/RIPK4/AMPK pathway. Fasudil may be a potential treatment for refractory wounds in diabetic patients.

DOI: 10.1038/s41401-024-01246-3

Source: https://www.nature.com/articles/s41401-024-01246-3