Hasanpour-Segherlou Zahra, Hutchinson Hunter, Xu Haiyan, Amini Shawna, Klaas Elizabeth, Martinez Melanie E, Lucke-Wold Brandon, Hosaka Koji, Hoh Brian
Department of Neurosurgery, University of Florida, Gainesville, Florida, USA.
Department of Neurosurgery, University of Florida, Gainesville, Florida, USA
J Neurointerv Surg. 2025 May 22. doi: 10.1136/jnis-2025-023108.
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.
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.
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.
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.
蛛网膜下腔出血（SAH）是一种危及生命的疾病，死亡率高且常伴有严重的神经功能障碍，常并发迟发性脑缺血（DCI）和血管痉挛。血红素代谢产物如胆绿素（BV）与SAH诱导的血管功能障碍有关，但将BV还原为胆红素的酶——胆绿素还原酶-A（BVR-A）的作用仍未得到充分研究。本研究调查了BV和BVR-A的氧化翻译后修饰对血管痉挛发展的影响。
我们使用了将BV注入蛛网膜下腔的小鼠模型，并分析其对血管痉挛、微血栓形成、神经元凋亡和小胶质细胞活化的影响。此外，使用免疫沉淀和蛋白质印迹技术，对有或无血管痉挛的SAH患者的人血浆和脑脊液（CSF）样本进行BVR-A表达和氧化修饰评估。
在小鼠模型中注射BV可诱导显著的血管痉挛，增加微血栓形成、神经元凋亡，并使小胶质细胞发生反应性形态改变。在人类样本中，尽管BVR-A表达水平相似，但与无血管痉挛的SAH患者相比，有血管痉挛的SAH患者血浆中BVR-A的氧化修饰显著升高。在CSF样本中未观察到氧化修饰的显著差异。
本研究显示了BV在血管痉挛发展中的新作用，并确定BVR-A的氧化修饰是SAH病理的潜在调节因子。这些发现表明，BV和BVR-A活性改变可能作为生物标志物或治疗靶点，以改善SAH患者的预后。
