Overexpression of LH3 reduces the incidence of hypertensive intracerebral hemorrhage in mice
Overexpression of LH3 reduces the incidence of hypertensive intracerebral hemorrhage in mice
复制标题
LH3过表达可降低小鼠高血压脑出血的发生率
DOI：
10.1177/0271678x18815791
复制
发表时间：
2019-03-01
影响因子：
6.3
通讯作者：
Chen, Jingzhou
中科院分区：
文献类型：
--
作者：
Li, Hao;Xu, Haochen;Chen, Jingzhou
高血压性脑出血是一种严重危害人类健康的脑血管疾病，目前尚无有效的治疗方法。赖氨酰羟基酶3(LH3)是IV型胶原分子间交联和稳定所必需的。LH3缺乏影响血管IV型胶原的组装和分泌以及基底膜(BM)的完整性。在这里，我们调查了LH3是否对疾病进展和治疗干预有重要意义。用血管紧张素II和L-NAME治疗诱导小鼠自发性高血压脑出血。通过立体定向注射将腺相关病毒送入脑内，以下调或过表达LH3。我们发现在人类脑出血患者体内LH3水平降低，在脑出血前小鼠体内LH3水平逐渐降低。LH3基因敲除增加了小鼠高血压脑出血的发生率。LH3过表达可显著降低ICH的发生率、数目和大小。RNA-SEQ显示，LH3的过表达显著逆转了脑血管基因转录谱的深刻变化。脑出血前LH3过表达足以增强骨髓完整性，抑制基质金属蛋白酶活性，减少小胶质细胞活化和白细胞浸润，减少VSMC的凋亡。这些结果表明，LH3的过表达降低了高血压脑出血的易感性。我们强调，LH3的调节可能是未来脑出血预防研究的一种可行的方法。
Hypertensive intracerebral hemorrhage (ICH) is a devastating cerebrovascular disease with no effective treatment. Lysyl hydroxylase 3 (LH3) is essential for collagen IV intermolecular crosslinking and stabilization. Deficiency in LH3 affects the assembly and secretion of collagen IV and basement membrane (BM) integrity of vessels. Here, we investigated whether LH3 has significant implications for disease progression and therapeutic intervention. Spontaneous hypertensive ICH of mice was induced by angiotensin II and L-NAME treatment. The adeno-associated virus was delivered into brain by stereotactic injection to knockdown or overexpress LH3. We found LH3 levels were reduced in human patients with ICH and gradually decreased in mice before ICH. LH3 knockdown increased the incidence of hypertensive ICH in mice. The incidence, number, and size of ICHs in mice were markedly reduced by LH3 overexpression. RNA-seq revealed that LH3 overexpression significantly reversed the profound alterations in gene transcriptional profiles of cerebral vessels. LH3 overexpression was sufficient to enhance BM integrity, inhibit matrix metalloproteinase activity, attenuate microglial activation and leukocyte infiltration, and reduce VSMC apoptosis before ICH. These results indicate that LH3 overexpression attenuates susceptibility to hypertensive ICH. We emphasize that LH3 modulation may serve as a viable approach for future investigations of ICH prevention.