MiRNA let-7b promotes the development of hypoxic pulmonary hypertension by targeting ACE2

• Published in: American journal of physiology. Lung cellular and molecular physiology 2019-03, Vol.316 (3), p.L547-L557
• Main Authors: Zhang, Ruifeng, Su, Hua, Ma, Xiuqing, Xu, Xiaoling, Liang, Li, Ma, Guofeng, Shi, Liuhong
• Format: Article
• Language: English
• Subjects: Animals; Cell Proliferation - physiology; Gene Knockout Techniques; Hypertension, Pulmonary - genetics; Hypertension, Pulmonary - metabolism; Hypoxia - genetics; Hypoxia - metabolism; Lung - metabolism; Male; MicroRNAs - genetics; Myocytes, Smooth Muscle - metabolism; Peptidyl-Dipeptidase A - genetics; Pulmonary Artery - pathology; Rats, Sprague-Dawley; Vascular Remodeling - genetics; Vascular Remodeling - physiology
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00387.2018

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.