Collagen glycation-mediated mechanical stress aggravates ischemia-reperfusion injury.

Abstract

Ischemia-reperfusion (IR) injury is a grave concern because of its substantial risk of organ failure in organ transplantation. Understanding its mechanism is essential for exploring potential management strategies to alleviate IR injury. In this study, we investigate the development of IR injury from a biomechanical perspective. Our results reveal a significant increase in tissue stiffness in IR- affected areas, driven by extracellular matrix crosslinking through collagen glycation. A stiffened matrix induces mechanical stretch, leading to excessive intracellular force transmission, which triggers apoptosis and worsen tissue injury. In livers with substantial collagen accumulation, such as those with fibrosis or aging, ischemia-reperfusion results in increased collagen glycation, pronounced abnormal mechanical signaling, and severe damage. Importantly, our data further demonstrate that intercepting mechanical force transduction effectively alleviate hepatic IR injury. This work deepens the understanding of IR development from a biomechanical perspective and provides new insights into future IR injury management. STATEMENT OF SIGNIFICANCE: Transplantation is a common treatment for various end-stage diseases. However, ischemia reperfusion injury during transplant procedures poses a risk of organ failure in patients. Unraveling the molecular mechanisms behind this process is of significant clinical importance. Our study innovatively demonstrates that ischemia reperfusion leads to an increase in extracellular matrix stiffness, which induces mechanical stress and promotes cell death, thereby exacerbating ischemia reperfusion injury. Inhibition of abnormal mechanical signaling was found to alleviate this injury, this offered a new therapeutic approach for managing ischemia reperfusion in the future.