P2X7 receptor regulates EMMPRIN and MMP‑9 expression through AMPK/MAPK signaling in PMA‑induced macrophages

Lin,Lu; Huang,Shanjun; Zhu,Zhouyang; Han,Jibo; Wang,Zhengxian; Huang,Weijian; Huang,Zhouqing

doi:10.3892/mmr.2018.9282

P2X7 receptor regulates EMMPRIN and MMP‑9 expression through AMPK/MAPK signaling in PMA‑induced macrophages

Authors:
- Lu Lin
- Shanjun Huang
- Zhouyang Zhu
- Jibo Han
- Zhengxian Wang
- Weijian Huang
- Zhouqing Huang
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Affiliations: The Key Laboratory of Cardiovascular Disease of Wenzhou, Department of Cardiology, Cardiac Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
Published online on: July 16, 2018 https://doi.org/10.3892/mmr.2018.9282
Pages: 3027-3033

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Abstract

The rupture of atherosclerotic plaques may result in the formation of thrombi, which may induce subsequent cardiac events such as acute myocardial infarction. Overproduction of matrix metalloproteinases (MMPs) and extracellular matrix metalloproteinase inducers (EMMPRINs) by monocytes and macrophages may lead to rupture of atherosclerotic plaques as a result of the degradation of the extracellular matrix. The purinergic 2X7 receptor (P2X7R) is expressed in macrophages that are assembled in atherosclerotic lesions of human carotid arteries. P2X7R may serve a crucial role in the development of atherosclerosis; therefore, the present study aimed to determine whether P2X7R regulated the expression of EMMPRIN and MMP‑9 in phorbol 12‑myristate 13‑acetate (PMA)‑induced macrophages. In addition, the potential molecular mechanisms involved in this process were investigated. THP‑1 human monocytic cells were pretreated with A‑438079 (a specific inhibitor of P2X7R) for 1 h and subsequently incubated with or without PMA for 48 h. Exposure to A‑438079 significantly decreased the expression of MMP‑9 and EMMPRIN in the PMA‑induced macrophages and attenuated the activation (phosphorylation) of mitogen‑activated protein kinase (MAPK) signaling, including c‑Jun N‑terminal kinase, p38 and extracellular signal‑regulated kinase. The present study also demonstrated that 5'‑AMP‑activated protein kinase (AMPK) was activated by PMA exposure during differentiation from monocytes to macrophages. This activation was reversed by A‑438079 treatment through the inhibition of P2X7R expression. These results suggested that the inhibition of P2X7R may be able to suppress the AMPK/MAPK signaling pathway and consequently downregulate both EMMPRIN and MMP‑9 expression in PMA‑induced macrophages.

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