儿茶酚抑素在大鼠间歇低氧性肺动脉高压发生发展中的作用及机制

The main pathological feature of hypoxic pulmonary hypertension (HPH) is pulmonary vasoconstriction and pulmonary vascular remodeling. At present it is considered that sympathetic adrenal medulla system sustained excitement and pulmonary vascular endothelial cell injury play an important role in the pathogenesis of HPH. Catestatin , a newly discovered active peptide, is an endogenous blockers of catecholamine release. It may have a wide range of cardiovascular protective effects. But there is no reports that introduces the relationship between catestatin and HPH. We observed in preliminary experiments that rat exposed in intermittent hypoxia environment have a less expression of catestatin protein in its right ventricular tissue. We also discover that catestatin had an effect of diastolic isolated pulmonary arterial rings in normal rats, suggesting that the catestatin may have a close relationship with the process of HPH. As the catestatin can play a role in many processes of PHP development, it may be a new targets for prevention and treatment of HPH.This study intends to dynamically observe the expression changes of the catestatin gene and protein in HPH rats, as well as given exogenous catestatin, to clarify its effect on HPH occurrence and development, and the effect of prevention and control during the development. And at entirety, isolated pulmonary arterial rings and cell levels, and to clarify its mechanisms which may related with the restrain of endogenous catecholamines release, the reduction of pulmonary artery systolic and diastolic abnormalities caused by hypoxia and the protective action for pulmonary vascular endothelial cell by initiating phosphatidyl-inositide 3 kinase/Akt(PI3K/Akt) pathway.

低氧性肺动脉高压（HPH）的主要病理特征是肺血管收缩反应性增强和肺血管改建。迄今认为交感-肾上腺髓质系统的兴奋，肺血管内皮细胞损伤在HPH的发病机制中起了重要的作用。儿茶酚抑素是内源性儿茶酚胺释放抑制剂，是新发现的一种可能具有广泛心血管保护作用的活性肽。但目前尚无与HPH有关的报道。我们预实验观察到儿茶酚抑素具有舒张正常大鼠离体肺动脉环的作用，低氧大鼠右心室肌儿茶酚抑素蛋白表达下调，提示儿茶酚抑素可能与HPH进程密切相关。由于儿茶酚抑素能作用于HPH的多个环节，推测其可能是防治HPH的新靶点。本研究拟动态观察低氧大鼠体内儿茶酚抑素的基因和蛋白的表达变化，以及外源性给予儿茶酚抑素，以阐明其在HPH发生发展中的作用及防治的效果。并从整体、离体肺动脉环和细胞层面上，阐明其作用机制可能与抑制内源性儿茶酚胺的释放、减轻低氧所致的肺血管舒缩异常、通过活化磷脂酰肌醇3激酶/蛋白激酶通路保护内皮细胞等有关

低氧可引起交感神经兴奋性增高，导致血管持续性收缩,进而引起肺细小动脉血管重塑，肺动脉压升高。儿茶酚抑素（catestatin，CST）可抑制交感神经兴奋引起的儿茶酚胺类物质的释放，推测其可能在间歇低氧导致的肺动脉高压的发病中起重要作用。本课题组发现：①在慢性间歇低氧及长期低氧性肺动脉高压大鼠模型上均发现，低氧组大鼠血浆中儿茶酚胺水平上调，肾交感神经放电活动增强，而血浆中CST含量下调；相关分析发现，低氧组大鼠的平均肺动脉压与动脉血浆中CST水平呈显著负相关，与体内儿茶酚胺含量呈显著正相关；低氧组大鼠肺组织及右心室中CST的前体蛋白Chga的蛋白以及基因表达明显低于常氧对照组；表明内源性CST参与了大鼠低氧性肺动脉高压的发生，血浆中CST与儿茶酚胺的失平衡在大鼠间歇低氧性肺动脉高压可能起重要作用。②在大鼠低氧的同时外源性给予CST，结果发现外源性CST具有防治慢性常压间歇低氧性肺动脉高压大鼠的作用。③在整体动物模型和离体培养的肺血管内皮细胞上进一步发现外源性CST具有促进大鼠肺血管内皮细胞的增殖作用，即修复了缺氧造成的肺血管内皮细胞损伤；外源性CST能通过活化磷脂酰肌醇-3激酶/蛋白激酶(PI3K/Akt)信号，促进肺动脉内皮细胞中内皮型一氧化氮合酶（eNOS）磷酸化，合成释放NO，从而减轻慢性低氧性肺动脉高压大鼠发展的进程。④另外，课题组在临床睡眠呼吸暂停综合征患者上发现，睡眠呼吸暂停综合征患者血浆中的CST水平显著降低，而儿茶酚胺水平显著升高；血浆中CST浓度与动脉血氧浓度呈正相关，而与体重指数、呼吸暂停低通气指数、AHI分级、呼吸紊乱指数、呼吸暂停指数呈负相关；进一步研究发现CST在睡眠呼吸暂停综合征中可能与抗氧化损伤机制以及Nrf2-ARE信号通路有关。通过以上研究可知，儿茶酚抑素可能是慢性间歇低氧性肺动脉高压和间歇低氧睡眠呼吸暂停综合征发病的交感神经机制中的内源性调节机制，为今后临床上有效诊断和治疗提供了新的依据。