Leptin upregulates smooth muscle cell expression of MMP‑9 to promote plaque destabilization by activating AP‑1 via the leptin receptor/MAPK/ERK signaling pathways

Liu,Ruijie; Chen,Benfa; Chen,Jiemin; Lan,Jun

doi:10.3892/etm.2018.6853

Leptin upregulates smooth muscle cell expression of MMP‑9 to promote plaque destabilization by activating AP‑1 via the leptin receptor/MAPK/ERK signaling pathways

Authors:
- Ruijie Liu
- Benfa Chen
- Jiemin Chen
- Jun Lan
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Affiliations: Department of Cardiology, Dongguan Third People's Hospital, Dongguan, Guangdong 523326, P.R. China, Department of Cardiology, Donghua Hospital of Sun Yat‑sen University, Dongguan, Guangdong 523326, P.R. China
Published online on: October 12, 2018 https://doi.org/10.3892/etm.2018.6853
Pages: 5327-5333

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Abstract

Leptin has been reported to be expressed in carotid atherosclerotic plaques, where it can promote lesion instability. Matrix metalloproteinases (MMPs) produced by smooth muscle cells (SMCs) are known to contribute to the weakening of atherosclerotic plaques via the degradation of extracellular matrix (ECM) proteins. The present study investigated whether leptin promotes plaque rupture by increasing the expression of MMP in SMCs in vivo and in vitro. In vivo, the neointima/media ratio and expression of MMP in the carotid artery of ob/ob mice were measured following carotid ligation and systemic administration of leptin. In vitro, the effect of leptin treatment on the expression of MMP in isolated SMCs and the underlying signaling pathways were investigated by gelatin zymography and western blot analysis. The results demonstrated that leptin treatment significantly increased the neointima/media ratio and expression of MMP‑9 in the carotid artery of mice following carotid ligation. In vitro, leptin also significantly increased the expression and activity of MMP‑9 in cultured SMCs in a dose‑dependent manner. Leptin also increased the production of MMP‑9 by activating leptin receptor and mitogen‑activated protein kinases, including extracellular signal‑regulated kinase (ERK) and c‑Jun N‑terminal kinase (JNK), which in turn enhanced the binding of the transcription factor activator protein‑1 (AP‑1) to the MMP‑9 promoter. The inhibition of leptin‑activated phosphorylation of ERK and JNK suppressed the leptin‑stimulated expression of AP‑1 and MMP‑9. Leptin treatment induced the expression of MMP‑9 in SMCs, suggesting that leptin may have substantial involvement in plaque rupture by promoting the degradation of ECM.

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