Proteasome inhibitor bortezomib prevents proliferation and migration of pulmonary arterial smooth muscle cells

Author:

Liu Yi‐Ching1,Tseng Yu‐Hsin1ORCID,Kuan Yu‐Hsin2,Wang Lin‐Yen3456,Huang Shang‐En7,Tsai Siao‐Ping8,Yeh Jwu‐Lai791011,Hsu Jong‐Hau18ORCID

Affiliation:

1. Department of Pediatrics, Kaohsiung Medical University Hospital Kaohsiung Medical University Kaohsiung Taiwan

2. Department of Medical Research, E‐Da Hospital I‐Shou University Kaohsiung Taiwan

3. Department of Pediatrics Chi‐Mei Medical Center Tainan Taiwan

4. School of Medicine, College of Medicine National Sun Yat‐sen University Kaohsiung Taiwan

5. School of Medicine, College of Medicine Kaohsiung Medical University Kaohsiung Taiwan

6. Department of Childhood Education and Nursery Chia Nan University of Pharmacy and Science Tainan Taiwan

7. Department of Pharmacology, College of Medicine Kaohsiung Medical University Kaohsiung Taiwan

8. Department of Pediatrics, School of Medicine, College of Medicine Kaohsiung Medical University Kaohsiung Taiwan

9. Department of Medical Research Kaohsiung Medical University Hospital Kaohsiung Taiwan

10. Graduate Institute of Medicine Kaohsiung Medical University Kaohsiung Taiwan

11. Department of Marine Biotechnology and Resources National Sun Yat‐sen University Kaohsiung Taiwan

Abstract

AbstractPulmonary vascular remodeling is a key pathological process of pulmonary arterial hypertension (PAH), characterized by uncontrolled proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). Bortezomib (BTZ) is the first Food and Drug Administration (FDA)‐approved proteasome inhibitor for multiple myeloma treatment. Recently, there is emerging evidence showing its effect on reversing PAH, although its mechanisms are not well understood. In this study, anti‐proliferative and anti‐migratory effects of BTZ on PASMCs were first examined by different inducers such as fetal bovine serum (FBS), angiotensin II (Ang II) and platelet‐derived growth factor (PDGF)‐BB, while potential mechanisms including cellular reactive oxygen species (ROS) and mitochondrial ROS were then investigated; finally, signal transduction of ERK and Akt was examined. Our results showed that BTZ attenuated FBS‐, Ang II‐ and PDGF‐BB‐induced proliferation and migration, with associated decreased cellular ROS production and mitochondrial ROS production. In addition, the phosphorylation of ERK and Akt induced by Ang II and PDGF‐BB was also inhibited by BTZ treatment. This study indicates that BTZ can prevent proliferation and migration of PASMCs, which are possibly mediated by decreased ROS production and down‐regulation of ERK and Akt. Thus, proteasome inhibition can be a novel pharmacological target in the management of PAH.

Funder

Kaohsiung Medical University Chung-Ho Memorial Hospital

National Science and Technology Council

Publisher

Wiley

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