Department of Respiratory Medicine, Sir Run Run Shaw Hospital, Medical School of Zhejiang University , Hangzhou , China.
Department of Ultrasound, Second Affiliated Hospital, Medical School of Zhejiang University , Hangzhou , China.
Am J Physiol Lung Cell Mol Physiol. 2019 Mar 1;316(3):L547-L557. doi: 10.1152/ajplung.00387.2018. Epub 2019 Jan 10.
Angiotensin-converting enzyme 2 (ACE2) protects against hypoxic pulmonary hypertension (HPH) by inhibiting the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). Under hypoxia, the hypoxia-inducible factor 1α (HIF-1α) inhibits ACE2 indirectly; however, the underlying mechanism is unclear. In the present study, we found that exposure to chronic hypoxia stimulated microRNA (miRNA) let-7b expression in rat lung via a HIF-1α-dependent pathway. Let-7b downregulated ACE2 expression by directly targeting the coding sequence of ACE2. Our in vitro and in vivo results revealed that let-7b contributed to the pathogenesis of HPH by inducing PASMCs proliferation and migration. Let-7b knockout mitigated right ventricle hypertrophy and pulmonary vessel remodeling in HPH by restoring ACE2 expression. Overall, we demonstrated that HIF-1α inhibited ACE2 expression via the HIF-1α-let-7b-ACE2 axis, which contributed to the pathogenesis of HPH by stimulating PASMCs proliferation and migration. Since let-7b knockout alleviated the development of HPH, let-7b may serve as a potential clinical target for the treatment of HPH.
血管紧张素转换酶 2（ACE2）通过抑制肺动脉平滑肌细胞（PASMC）的增殖和迁移来预防低氧性肺动脉高压（HPH）。在低氧环境下，缺氧诱导因子 1α（HIF-1α）通过间接途径抑制 ACE2；然而，其潜在机制尚不清楚。在本研究中，我们发现慢性低氧刺激通过 HIF-1α 依赖途径刺激大鼠肺中 microRNA（miRNA）let-7b 的表达。let-7b 通过直接靶向 ACE2 的编码序列下调 ACE2 的表达。我们的体外和体内结果表明，let-7b 通过诱导 PASMCs 的增殖和迁移参与 HPH 的发病机制。let-7b 敲除通过恢复 ACE2 的表达减轻 HPH 中的右心室肥大和肺血管重塑。总的来说，我们证明 HIF-1α 通过 HIF-1α-let-7b-ACE2 轴抑制 ACE2 的表达，通过刺激 PASMCs 的增殖和迁移促进 HPH 的发病机制。由于 let-7b 敲除减轻了 HPH 的发展，let-7b 可能成为治疗 HPH 的潜在临床靶点。
