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PM2.5 causes vascular hyperreactivity through the upregulation of the thromboxane A2 receptor and activation of MAPK pathways

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Abstract

Airborne fine particulate matter (PM2.5) is a major cardiovascular disease environmental risk factor. However, the underlying mechanism of action is not fully understood. Thromboxane is widely known as an important vasoconstrictor substance that binds to G-protein-coupled receptors (GPCR) in arteries and is involved in various cardiovascular diseases. This study examined the effect of PM2.5 on thromboxane A2 receptor (TP) in the mesenteric arteries and the underlying intracellular signal mechanisms (by focusing on the mitogen-activated protein kinase (MAPK) pathway). Rat mesenteric artery segments were exposed to PM2.5 in the presence of MAPK pathway inhibitors. The contractile reactivity of mesenteric arteries was analyzed using wire myography. The mRNA and protein expression of TP receptor and MAPK pathway molecules were detected by real-time PCR and Western blot. Mesenteric artery receptor localization was assessed by immunohistochemistry. The results showed that TP receptor-mediated maximum contraction response was achieved after exposing arteries to 1.0 μg/mL PM2.5 for 16 h (Emax: 228 ± 16% of K+). Moreover, inhibitor U0126 (ERK1/2 inhibitor), SB203580 (p38 inhibitor), and SP600125 (JNK inhibitor) depressed the increased TP receptor-mediated contractile responses (reduced rage were 17.9 ~ 59.6%). These inhibitors also decreased the increased mRNA expression and protein of the TP receptor induced by PM2.5 (reduced by more than 50% and 46%, respectively). The immunoreactivity of increased TP receptor expression was primarily localized in the cytoplasm. In addition, phosphorylation quantitative analysis showed that in the presence of MAPK inhibitors, the PM2.5-induced phosphorylation of ERK1/2, p38, and JNK protein increased by more than 30.0 ~ 130.3%. These results suggest that PM2.5 upregulates the TP receptor of rat mesenteric arteries through activation of the ERK1/2, p38, and JNK MAPK pathways.

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Funding

This work was supported by the National Natural Science Foundation of China (81903288), Science and Technology Innovation Team Xi’an Medical University (2021TD03), and the Key Research and Development Program of Shaanxi (No. 2021ZDLSF03-05).

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Authors and Affiliations

  1. Department of Pharmacology, Xi’an Medical University, 1 Xin Wang Road, Xi’an, 710021, Shaanxi, China

    Rong Wang, Kuan Yang, Nana Wang & Bei Qin

  2. Shaanxi Provincial Research Center for the Project of Prevention and Treatment of Respiratory Diseases, Xi’an Medical University, Xi’an, Shaanxi, China

    Rong Wang

  3. Xi’an Children’s Hospital, Xi’an, Shaanxi, China

    Jinhui Wang

  4. Department of Environmental Science and Engineering, Xi’an Jiaotong University, Xi’an, Shaanxi, China

    Jian Sun

Authors
  1. Rong Wang
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  2. Jinhui Wang
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  3. Jian Sun
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  4. Kuan Yang
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  5. Nana Wang
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  6. Bei Qin
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Contributions

Rong Wang performed and designed the experiments and drafted the manuscript. Jinhui Wang provided the software and data analysis. Jian Sun collected and analyzed the PM2.5 samples. Kuan Yang and Nana Wang contributed to the molecular analysis. Bei Qin supervised the whole work and designed the experiments.

Corresponding author

Correspondence to Bei Qin.

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Ethical approval

The experimental design was approved by the ethics committee of Xi’an Medical University (approval no. XYLS2019070).

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The authors declare no competing interests.

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Responsible Editor: Ludek Blaha

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Wang, R., Wang, J., Sun, J. et al. PM2.5 causes vascular hyperreactivity through the upregulation of the thromboxane A2 receptor and activation of MAPK pathways. Environ Sci Pollut Res 29, 33095–33105 (2022). https://doi.org/10.1007/s11356-021-18303-7

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  • DOI: https://doi.org/10.1007/s11356-021-18303-7

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