Role of biliverdin reductase, a heme degradation pathway enzyme, in the development of vasospasm after subarachnoid hemorrhage.

Abstract

BACKGROUND: Subarachnoid hemorrhage (SAH) is a life-threatening condition with high mortality and significant neurological morbidity, often complicated by delayed cerebral ischemia (DCI) and vasospasm. Heme metabolites such as biliverdin (BV) are implicated in SAH-induced vascular dysfunction, yet the role of biliverdin reductase-A (BVR-A), an enzyme that reduces BV to bilirubin, remains underexplored. This study investigates the contribution of BV and oxidative post-translational modifications of BVR-A to vasospasm development. METHODS: We used a murine model of BV injection into the subarachnoid space and analyzed its effects on vasospasm, microthrombosis, neuronal apoptosis, and microglial activation. Additionally, human plasma and cerebrospinal fluid (CSF) samples from patients with SAH with and without vasospasm were evaluated for BVR-A expression and oxidative modifications using immunoprecipitation and western blot techniques. RESULTS: BV injection in the murine model induced significant vasospasm, increased microthrombosis, neuronal apoptosis, and a reactive morphological shift in microglia. In human samples, oxidative modifications of BVR-A were significantly raised in plasma from patients with SAH with vasospasm compared with those without, despite similar BVR-A expression levels. No significant differences in oxidative modifications were observed in CSF samples. CONCLUSION: This study shows a novel role of BV in vasospasm development and identifies oxidative modifications of BVR-A as potential modulators of SAH pathology. These findings suggest that BV and altered BVR-A activity may serve as biomarkers or therapeutic targets for improving outcomes in patients with SAH.