Pediatric Center of Cardiac Surgery, Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100037, China.
Chin Med J (Engl). 2012 Apr;125(8):1381-8.
Increasing evidences indicate that an activated renin-angiotensin system (RAS) causes an imbalance between the vasoconstrictive and vasodilator mechanisms involving the pulmonary circulation leading to the development of pulmonary arterial hypertension (PAH). Angiotensin-converting enzyme 2 (ACE2), a primary component of the vasoprotective axis in RAS, is recently identified that it has regulatory actions in lung pathophysiology, but the mechanism in these processes is uncertain yet.
Severe PAH was induced by monocrotaline injection one week following pneumonectomy in rats. The activation of ACE2 by continuous injection of resorcinolnaphthalein was studied by real time-polymerase chain reaction (RT-PCR), Western blotting and fluorogenic peptide assay. Endothelial functions were evaluated by the response to acetylcholine and cytokines were measured by RT-PCR seven days after monocrotaline injection. The PAH-related hemodynamics and pathological changes were examined at day 21 when severe PAH was completely established.
Resorcinolnaphthalein caused significant activation of ACE2 in both normal and diseased rats in 7 days after treatment. The pulmonary arterial pressure (PAP) started to increase at least 7 days after monocrotaline injection, and the rats developed severe PAH in 21 days with high PAP, right ventricular hypertrophy and neointimal formation. Treatment with resorcinolnaphthalein prevented these features. Resorcinolnaphthalein caused an improved endothelia-dependent vasorelaxation and decrease in proinflammatory cytokines (tumor necrosis factor (TNF)-α, monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-6) and increase in anti-inflammatory cytokine IL-10 in the early stage of the pathogenesis.
These results demonstrated that activation of ACE2 by continuous injection of resorcinolnaphthalein prevented the development of PAH through improving early endothelial dysfunction and mediating the level of proinflammatory and anti-inflammatory cytokines.
越来越多的证据表明，激活的肾素-血管紧张素系统（RAS）导致肺循环中血管收缩和血管舒张机制之间的失衡，导致肺动脉高压（PAH）的发展。血管紧张素转换酶 2（ACE2）是 RAS 中血管保护轴的主要组成部分，最近被发现它在肺病理生理学中有调节作用，但这些过程中的机制尚不确定。
在大鼠单侧肺切除后一周通过注射单硝酸异山梨酯诱导严重 PAH。通过实时聚合酶链反应（RT-PCR）、Western blot 和荧光肽测定研究间苯二酚萘酚对 ACE2 的激活作用。通过注射单硝酸异山梨酯 7 天后的乙酰胆碱反应评估内皮功能，通过 RT-PCR 测量细胞因子。在严重 PAH 完全建立的第 21 天检查 PAH 相关的血液动力学和病理变化。
间苯二酚萘酚在治疗后 7 天内可显著激活正常和患病大鼠的 ACE2。单硝酸异山梨酯注射后至少 7 天肺动脉压（PAP）开始升高，21 天大鼠发展为严重 PAH，伴有高 PAP、右心室肥厚和新生内膜形成。间苯二酚萘酚治疗可预防这些特征。间苯二酚萘酚可改善早期内皮依赖性血管舒张，并降低促炎细胞因子（肿瘤坏死因子（TNF）-α、单核细胞趋化蛋白-1（MCP-1）、白细胞介素（IL）-6）和增加抗炎细胞因子 IL-10 在发病早期。
这些结果表明，通过连续注射间苯二酚萘酚激活 ACE2，可通过改善早期内皮功能障碍和调节促炎和抗炎细胞因子水平来预防 PAH 的发展。
