Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
Department of Pediatrics, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Int J Med Sci. 2020 Sep 16;17(16):2594-2602. doi: 10.7150/ijms.48096. eCollection 2020.
Pulmonary hypertension (PH) is a lethal and rapidly progressing disorder if left untreated, but there is still no definitive therapy. An imbalance between vasoconstriction and vasodilation has been proposed as the mechanism underlying PH. Among the vasomediators of the pulmonary circulation is the renin-angiotensin system (RAS), the involvement of which in the development of PH has been proposed. Within the RAS, angiotensin-converting enzyme 2 (ACE2), which converts angiotensin (Ang) II into Ang-(1-7), is an important regulator of blood pressure, and has been implicated in cardiovascular disease and PH. In this study, we investigated the effects of the ACE2 activator diminazene aceturate (DIZE) on the development of PH secondary to left ventricular dysfunction. A model of PH secondary to left ventricular dysfunction was established in 6-week-old Wistar rats by ascending aortic banding for 42 days. The hemodynamics and pulmonary expression of ACE, Ang II, ACE2, Ang-(1-7), and the Ang-(1-7) MAS receptor were investigated in the early treatment group, which was administered DIZE (15 mg/kg/day) from days 1 to 42, and in the late treatment group, administered DIZE (15 mg/kg/day) from days 29 to 42. Sham-operated rats served as controls. DIZE ameliorated mean pulmonary artery pressure, pulmonary arteriolar remodeling, and plasma brain natriuretic peptide levels, in addition to reversing the overexpression of ACE and up-regulation of both Ang-(1-7) and MAS, in the early and late treatment groups. DIZE has therapeutic potential for preventing the development of PH secondary to left ventricular dysfunction through ACEII activation and the positive feedback of ANG-(1-7) on the MAS receptor. A translational study in humans is needed to substantiate these findings.
肺动脉高压（PH）如果不治疗，是一种致命且迅速进展的疾病，但目前仍没有明确的治疗方法。血管收缩和血管舒张之间的失衡被认为是 PH 的发病机制。在肺循环的血管活性物质中，肾素-血管紧张素系统（RAS）参与其中，其在 PH 的发展中的作用已被提出。在 RAS 中，血管紧张素转换酶 2（ACE2）将血管紧张素（Ang）II 转化为 Ang-（1-7），是血压的重要调节剂，并与心血管疾病和 PH 有关。在这项研究中，我们研究了 ACE2 激活剂地拉佐明（DIZE）对左心室功能障碍继发 PH 的发展的影响。通过升主动脉缩窄 42 天，在 6 周龄 Wistar 大鼠中建立了左心室功能障碍继发 PH 的模型。在早期治疗组和晚期治疗组中，我们研究了 ACE、Ang II、ACE2、Ang-（1-7）和 Ang-（1-7）MAS 受体在血液动力学和肺组织中的表达，早期治疗组从第 1 天至第 42 天给予 DIZE（15mg/kg/天），晚期治疗组从第 29 天至第 42 天给予 DIZE（15mg/kg/天）。假手术大鼠作为对照组。DIZE 改善了平均肺动脉压、肺小动脉重构和血浆脑钠肽水平，同时逆转了 ACE 的过度表达和 ACE2 和 MAS 受体的上调，在早期和晚期治疗组中。DIZE 通过 ACEII 激活和 ANG-（1-7）对 MAS 受体的正反馈，具有预防左心室功能障碍继发 PH 发展的治疗潜力。需要进行人类的转化研究来证实这些发现。
