Int J Biol Sci 2022; 18(1):331-348. doi:10.7150/ijbs.66472 This issue

Research Paper

MMP-10 from M1 macrophages promotes pulmonary vascular remodeling and pulmonary arterial hypertension

Pei-Ling Chi1,2, Chin-Chang Cheng3, Cheng-Chung Hung3, Mei-Tzu Wang3, Hsien-Yueh Liu4, Meng-Wei Ke5, Min-Ci Shen3, Kun-Chang Lin3, Shu-Hung Kuo3, Pin-Pen Hsieh6,7, Shue-Ren Wann8, Wei-Chun Huang3,9,10,11✉

1. Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung City 81362, Taiwan
2. Department of Pathology and Laboratory Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
3. Department of Critical Care Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 81362, Taiwan
4. Bachelor Degree Program in Animal Healthcare, Hungkuang University, Taichung City, Taiwan
5. The Agricultural College, Tunghai University, Taichung City, Taiwan
6. Department of Anatomic Pathology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-yi, Taiwan
7. School of Medicine, Tzu Chi University, Hualien, Taiwan
8. Pingtung Branch, Kaohsiung Veterans General Hospital, Pingtung County, Taiwan
9. Department of Physical Therapy, Fooyin University, Kaohsiung, Taiwan
10. School of Medicine, National Yang-Ming University, Taipei, Taiwan
11. Graduate Institute of Clinical Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan

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Citation:
Chi PL, Cheng CC, Hung CC, Wang MT, Liu HY, Ke MW, Shen MC, Lin KC, Kuo SH, Hsieh PP, Wann SR, Huang WC. MMP-10 from M1 macrophages promotes pulmonary vascular remodeling and pulmonary arterial hypertension. Int J Biol Sci 2022; 18(1):331-348. doi:10.7150/ijbs.66472. Available from https://www.ijbs.com/v18p0331.htm

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Abstract

Graphic abstract

Pulmonary arterial hypertension (PAH) is characterized by muscularized pulmonary blood vessels, leading to right heart hypertrophy and cardiac failure. However, state-of-the-art therapeutics fail to target the ongoing remodeling process. Here, this study shows that matrix metalloproteinases (MMP)-1 and MMP-10 levels are increased in the medial layer of vessel wall, serum, and M1-polarized macrophages from patients with PAH and the lungs of monocrotaline- and hypoxia-induced PAH rodent models. MMP-10 regulates the malignant phenotype of pulmonary artery smooth muscle cells (PASMCs). The overexpression of active MMP-10 promotes PASMC proliferation and migration via upregulation of cyclin D1 and proliferating cell nuclear antigen, suggesting that MMP-10 produced by infiltrating macrophages contributes to vascular remodeling. Furthermore, inhibition of STAT1 inhibits hypoxia-induced MMP-10 but not MMP-1 expression in M1-polarized macrophages from patients with PAH. In conclusion, circulating MMP-10 could be used as a potential targeted therapy for PAH.

Keywords: MMP-10, pulmonary arterial hypertension, M1 macrophges, vascular remodeling, pulmonary arterial smooth muscle cells