Hypoxia inducible factor-1alpha expression correlates with inflammatory injury of blood-brain barrier which influences perihaematomal edema after intracerebral hemorrhage

Abstract

Backround

In patients with intracerebral hemorrhage (ICH), perihematomal edema (PHE) significantly worsens the prognosis. This condition leads to the formation of a hypoxic microenvironment surrounding the blood-brain barrier (BBB), which in turn activates hypoxia-inducible factor-1 alpha (HIF-1α), a highly sensitive hypoxia-related transcription factor. Additionally, tumor necrosis factor-alpha (TNF-α) emerges as a promising biomarker for tracking inflammation in the vicinity of the BBB. The integrity of the BBB is maintained by proteins such as zonula occludens-1 (ZO-1), which is crucial for the tight junctions that regulate the barrier's permeability. Understanding these mechanisms is vital for developing targeted therapies to mitigate the effects of ICH.

Object

Through the collection and analysis of peripheral blood and tissue samples from ICH patients and animal models at predefined time points, we established the correlation between HIF-1α expression, inflammatory damage to the BBB, and the development of PHE.

Methods

Ethical approval was secured from relevant Chinese authorities and the Ethics Committee of Qinghai Provincial People's Hospital. The clinical study included 32 ICH patients, with computerized tomographic scans and blood samples taken at 1, 3, 7, and 14 days post-ICH. HIF-1α and ZO-1 expression, as well as TNF-α levels, were measured using enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, and western blot. In the animal study, 18 adult Sprague Dawley rats were divided into sham, ICH, and HIF-1α Inhibited groups. Lificiguat YC-1 was used to inhibit HIF-1α expression, and samples were collected at the critical change point identified clinically for similar measurements.

Results

At 3 days after onset, the highest level of HIF-1α and TNF-α, the lowest level of ZO-1 and the most obvious development in PHE appeared in ICH patients (F ≥ 10.278, P ≤ 0.004). At that day, HIF-1α expression positively correlated with TNF-α levels (r = 0.809, P<0.001); TNF-α negatively correlated with ZO-1 expression (r=-0.840, P<0.001) which negatively correlated with PHE development (r=-0.601, p<0.001). Comparing to sham group and sole ICH group, after HIF-1α expression was inhibited, all the biological indicators level of ICH rats were the lowest (F ≥ 14.953, p ≤ 0.005). Their correlation were the same as that in ICH patients.

Conclusion

At 3 days after onset of ICH, HIF-1α expression correlated with inflammatory injury of BBB, which influenced PHE.