Succinate metabolism and membrane reorganization drives the endotheliopathy and coagulopathy of traumatic hemorrhage

Abstract

Acute hemorrhage commonly leads to coagulopathy and organ dysfunction or failure. Recent evidence suggests that damage to the endothelial glycocalyx contributes to these adverse outcomes. The physiological events mediating acute glycocalyx shedding are undefined, however. Here, we show that succinate accumulation within endothelial cells drives glycocalyx degradation through a membrane reorganization-mediated mechanism. We investigated this mechanism in a cultured endothelial cell hypoxia-reoxygenation model, in a rat model of hemorrhage, and in trauma patient plasma samples. We found that succinate metabolism by succinate dehydrogenase mediates glycocalyx damage through lipid oxidation and phospholipase A2-mediated membrane reorganization, promoting the interaction of matrix metalloproteinase 24 (MMP24) and MMP25 with glycocalyx constituents. In a rat hemorrhage model, inhibiting succinate metabolism or membrane reorganization prevented glycocalyx damage and coagulopathy. In patients with trauma, succinate levels were associated with glycocalyx damage and the development of coagulopathy, and the interaction of MMP24 and syndecan-1 was elevated compared to healthy controls.

Relationship between serum sodium level and sepsis-induced coagulopathy

“…A study by Zheng et al ( 40 ) reported that, compared to the normal chow (NC) diet group, the NC diet with 4% salt (NC4%) induced microcirculatory disturbances and glycocalyx degradation in mice. Glycocalyx damage is closely associated with the development of coagulation dysfunction, which has also been reported in several papers ( 41–43 ). These findings may laterally indicate that elevated serum sodium levels impair eGC, which in turn affects coagulation.…”