赖氨酸羟化酶1（LH1）保护高血压脑出血血管病变的作用与机制

脑出血是脑卒中的第二大亚型，在所有脑卒中疾病中死亡率最高，给社会和家庭带来沉重的负担。赖氨酸羟化酶（LH）是一类调控胶原链接排序的酶,其中赖氨酸羟化酶-1（LH1）主要调控V型胶原。LH1的缺失会引发小鼠动脉畸形，导致胸腔和腹腔出血。申请人近期发现在小鼠自发高血压脑出血模型中LH1表达量随时间持续降低，推测LH1降低与脑出血发病存在密切关系。申请人利用腺相关病毒在小鼠脑血管过表达LH1，对小鼠进行高血压脑出血造模，通过生存曲线、MRI、病理切片染色证实过表达LH1能保护高血压脑出血的发生发展。本研究拟构建LH1基因敲除小鼠，通过高血压脑出血模型，探究小鼠脑血管的血脑屏障改变、细胞外基质重塑、血管炎症及平滑肌凋亡等层面，以阐释LH1调控高血压脑血管病变的作用及分子机制，为高血压脑出血的防控和干预提供新的思路。

Intracerebral hemorrhage (ICH), the second most common subtype of stroke, carries the highest mortality risk of all strokes and poses great burden to both society and individual. Lysyl hydroxylase (LH) is a type of enzyme responsible for collagen cross-link and deposition. The LH1 isoform is essential for collagen V intermolecular crosslinking and stabilization. Deficiency in LH1 causes aortic abnormalities in mice, which may lead to hemorrhages in the thoracic or abdominal cavity. Our recent preliminary studies found LH1 levels were reduced in mice model of hypertensive ICH and gradually decreased before ICH, which indicates the strong relationship between LH1 reduction with ICH. We constructed an AAV-LH1 vector to induce the exogenous expression of LH1 in cerebral vessel of mice, and generated mice model of hypertensive ICH. The incidence, number, and size of ICHs in mice were markedly reduced by LH1 overexpression, as validated by survival curve, MRI imaging, and histological staining. The current study aims to construct LH1 gene knockout mice and generate hypertensive intracerebral hemorrhage mice model, explore changes in BBB integrity, extracellular matrix remodeling, vascular inflammation, and vascular smooth muscle cell apoptosis. The findings will clarify the role and underlying mechanism of LH1 on hypertensive intracerebral hemorrhage vasculopathy, and provide new insights into the prevention and intervention of hypertensive ICH.