ROCK1 Inhibition Improves Wound Healing in Diabetes via RIPK4/AMPK Pathway

TL;DR: In this paper , the role of Rho-associated protein kinase-1 (ROCK1) in diabetic wound healing and molecular mechanisms was investigated and fasudil and ROCK1 siRNA significantly increased wound granulation tissues in both diabetic patients and diabetic mice.

Abstract: Abstract Background and Purpose: Refractory wounds are a severe complication of diabetes mellitus with limited treatment regimens. Rho-associated protein kinase-1 (ROCK1) phosphorylates a series of substrates that trigger downstream signaling pathways, affecting multiple cellular processes. The present study investigated the role of ROCK1 in diabetic wound healing and molecular mechanisms. Experimental Approach: Streptozotocin (STZ)-induced diabetic mice with full-thickness excisional wound model and human umbilical vein endothelial cells (HUVECs) were used. Key Results: ROCK1 expression significantly increased in wound granulation tissues in both diabetic patients and 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 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). Conclusion and Implications: 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.