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Extracellular matrix collagen biomarkers levels in patients with chronic thromboembolic pulmonary hypertension

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Abstract

Limited data exist on changes in the extracellular matrix (ECM) collagen biomarkers levels during chronic thromboembolic pulmonary hypertension (CTEPH) development. This study aimed to investigate ECM collagen biomarkers levels in stable patients with CTEPH. Patients with CTEPH and healthy persons were enrolled. Serum levels of procollagen III N-terminal peptide (PIIINP), carboxyterminal propeptide of type I procollagen (PICP), matrix metalloproteinases (MMP2), MMP9, and tissue inhibitor of metalloproteinases 1(TIMP1) were measured by ELISA. Clinical data coincident with samples were collected. The pulmonary endarterectomy (PEA) and control pulmonary artery tissue samples were analyzed for genetic and immunohistochemical differences. The serum concentrations of PIIINP, PICP, MMP2, and MMP9 decreased significantly in CTEPH patients compared to healthy controls (P < 0.001 for each). CTEPH patients had higher serum concentrations of TIMP1 (median, 111.97 [interquartile range, 84.35–139.93]) compared to healthy controls (74.97 [44.03–108.45] ng/mL, P < 0.001). The MMP2 to TIMP1 ratio was lower in patients than in the controls (P < 0.001). After adjusting for the body mass index (BMI), the MMP2 to TIMP1 ratio correlated negatively with pulmonary vascular resistance (PVR) (r = − 0.327, P = 0.025). Increased TIMP1 (P = 0.04) gene expression was identified in tissues of CTEPH patients. Immunohistochemistry results of vascular walls substantiated qRT-PCR results. This study indicates that ECM collagen biomarkers levels were significantly different in stable patients with CTEPH and healthy controls with significantly increased TIMP1 and decreased MMP2 and MMP9. Differences in TIMP1 expression should be expected not only among healthy controls and patients serum, but also across pathological tissue regions. These findings suggest that the state of vascular remodeling in pulmonary vascular bed in stable patients may be represented by ECM collagen biomarkers levels. We conclude that TIMP1 may play an important role in pulmonary vascular reconstruction in stable CTEPH patients.

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Funding

This study is fund by National Natural Science Foundation of China (Nos. 81570049, 81970058); Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (CIFMS) (No. 2018-I2M-1-003); Beijing Natural Science Foundation (No. 7152062).

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Authors and Affiliations

  1. Department of Pulmonary and Critical Care Medicine, Center of Respiratory Medicine, China-Japan Friendship Hospital, No 2, East Yinghua Road, Chaoyang District, Beijing, People’s Republic of China

    Wenyi Pang, Zhu Zhang, Yunxia Zhang, Meng Zhang, Wanmu Xie, Jun Wan, Zhenguo Zhai & Chen Wang

  2. National Center for Respiratory Medicine, Institute of Respiratory Medicine, Chinese Academy of Medical Sciences, National Clinical Research Center for Respiratory Diseases, No 2, East Yinghua Road, Chaoyang District, Beijing, People’s Republic of China

    Wenyi Pang, Zhu Zhang, Yunxia Zhang, Meng Zhang, Wanmu Xie, Jun Wan, Zhenguo Zhai & Chen Wang

  3. Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China

    Wenyi Pang, Zhu Zhang, Zhenguo Zhai & Chen Wang

  4. Beijing Institute of Respiratory Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, People’s Republic of China

    Ran Miao & Yuanhua Yang

  5. Department of Respiratory Medicine, Capital Medical University, Beijing, People’s Republic of China

    Ran Miao, Yuanhua Yang, Wanmu Xie, Jun Wan, Zhenguo Zhai & Chen Wang

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  1. Wenyi Pang
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  9. Zhenguo Zhai
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  10. Chen Wang
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Contributions

WP: Conception and design of the study; collection, analysis and interpretation of data; drafting of the manuscript; final approval of the manuscript. ZZ: Analysis and interpretation of data; drafting of the manuscript; final approval of the manuscript. YZ and MZ: Collection the surgical specimens; final approval of the manuscript. RM: Provide technical guidance and analysis of data; final approval of the manuscript. YY, JW, WX and CW: Participate in patients clinical data acquisition and interpret of the data; final approval of the manuscript. ZZ: Conception and design of the study; collection, analysis and interpretation of data; drafting of the manuscript; final approval of the manuscript.

Corresponding author

Correspondence to Zhenguo Zhai.

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All the procedures carried out with human data and samples were approved by the Ethics Committee of Hospital (Nos. 2015-S-53, 2019-121-K83) in accordance with the Declaration of Helsinki and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Pang, W., Zhang, Z., Zhang, Y. et al. Extracellular matrix collagen biomarkers levels in patients with chronic thromboembolic pulmonary hypertension. J Thromb Thrombolysis 52, 48–58 (2021). https://doi.org/10.1007/s11239-020-02329-8

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