Gene

microRNA

Angiotensin-converting enzyme 2

Cell biology

Biotechnology

Biology

Pulmonary artery

Receptor

Cancer research

Biochemistry

Hypoxia (environmental)

Knockout mouse

Coronavirus disease 2019 (COVID-19)

In vivo

Organic chemistry

Oxygen

Angiotensin II

Infectious disease (medical specialty)

Internal medicine

Pulmonary hypertension

Conditional gene knockout

Medicine

Chemistry

Right ventricular hypertrophy

Disease

Pathogenesis

Lung

Ventricle

Phenotype

AJP Lung Cellular and Molecular Physiology

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.

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