Emerging roles of let‑7d in attenuating pulmonary arterial hypertension via suppression of pulmonary artery endothelial cell autophagy and endothelin synthesis through ATG16L1 downregulation

Ou,Minghui; Li,Xia; Cui,Shichao; Zhao,Shibo; Tu,Jie

doi:10.3892/ijmm.2020.4567

Emerging roles of let‑7d in attenuating pulmonary arterial hypertension via suppression of pulmonary artery endothelial cell autophagy and endothelin synthesis through ATG16L1 downregulation

Authors:
- Minghui Ou
- Xia Li
- Shichao Cui
- Shibo Zhao
- Jie Tu
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Affiliations: Department of Vascular Surgery, Qingdao Municipal Hospital, Qingdao, Shandong 266011, P.R. China, Department of Ultrasound, Qingdao Municipal Hospital, Qingdao, Shandong 266011, P.R. China, Department of Science and Education, Qingdao Municipal Hospital, Qingdao, Shandong 266011, P.R. China
Published online on: April 7, 2020 https://doi.org/10.3892/ijmm.2020.4567
Pages: 83-96
Copyright: © Ou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Pulmonary arterial hypertension (PAH) is a severe disease characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance, resulting in right ventricular failure and death. Compelling evidence has suggested the roles of microRNAs (miRNAs/miRs) in PAH. The present study investigated the possible effects of miR‑let‑7d on PAH through autophagy‑related 16‑like 1 (ATG16L1). Initially, the serum levels of let‑7d in PAH patients were detected. Rats were then treated with monocrotaline to induce a rat model of PAH, after which the right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI) were determined. Next, the putative binding sites between let‑7d and ATG16L1 were detected. The expression of let‑7d and ATG16L1 in PAH rat models and cells was upregulated or downregulated to assess the effects of these molecules on autophagy in pulmonary artery vascular endothelial cells (PAECs) and on endothelin synthesis. In addition, the levels of p62, LC3‑I, LC3‑II, LC3B and endothelin‑1 (ET‑1) were assessed. The results obtained revealed that let‑7d was downregulated in the serum of PAH patients and rats with PAH. Importantly, ATG16L1 was found to be a target gene of let‑7d and let‑7d could suppress the expression of ATG16L1. Overexpression of let‑7d was found to reduce RVSP and RVHI values. Additionally, upregulation of let‑7d or depletion of ATG16L1 led to suppression of PAEC autophagy and endothelin synthesis, corresponding to decreased ratios of LC3‑II to LC3‑I and reduced levels of LC3B but elevated levels of p62 in PAECs and ET‑1 in plasma and lung tissues. In summary, let‑7d upregulation alleviates PAH by inhibiting autophagy in PAECs and suppressing endothelin synthesis through negative regulation of ATG16L1.

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