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

Abstract

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.