抑制LOXL2可以改善肺动脉重塑在肺高血压

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Jochen Steppan, Huilei Wang, Kavitha Nandakumar

bioRxiv : the preprint server for biology

|November 14, 2023

概括

像2 (LOXL2) 这样的lysyl氧化酶驱动肺高血压 (PH) 中的肺动脉硬化. 在PH模型中,用PAT-1251抑制LOXL2可以改善肺动脉功能和生存率.

科学领域:

血管生物学血管生物学
心血管研究的心血管研究.
肺高血压是一种肺高血压.

背景情况:

肺动脉硬化增加了肺血管阻抗,这是肺动脉高血压 (PAH) 的关键因素.
矩阵沉积驱动PAH中的血管重塑.
类似2的lysyl氧化酶 (LOXL2) 是一种原交联酶,涉及血管重塑.

研究的目的:

研究LOXL2在肺动脉硬化和PAH中的作用.
为了评估一种新型LOXL2抑制剂,PAT-1251.1.的治疗潜力.

主要方法:

在低氧状态下,评估了LOXL2分泌和表达在人类肺动脉光滑肌细胞 (PASMCs) 中.
肺动脉 (PAs) 和PH的老鼠模型肺中的量化LOXL2水平 (苏根5416 + 缺氧[SuHx]和单色素[MCT]).
评估了PA的机械性质 (刚性,收缩性,血管放松性) 和右心脏功能 in vivo 和 ex vivo.
用LOXL2抑制剂PAT-1251治疗PH大鼠,并评估生理和生存结果.

主要成果:

低氧增加了人类PASMC中的LOXL2分泌.
从老鼠PH模型中,LOXL2表达和活性在PA中升高.
PH大鼠表现出增加的PA刚性,超收缩性和内皮功能障碍.
PAT-1251治疗改善了PA的机械特性和内皮功能.
在体内,PAT-1251治疗改善了PH,改善了右心功能,并增加了存活率.

结论:

LOXL2激活是低氧诱导的肺动脉硬化和PH的功能下降的因果机制.
抑制LOXL2代表了PAH的一个有前途的治疗策略.
用PAT-1251针对LOXL2可以改善肺血液动力学,右心室功能和PH的存活率.

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