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  2. Increased hepcidin in hemorrhagic plaques correlates with iron-stimulated IL-6/STAT3 pathway activation in macrophages

Increased hepcidin in hemorrhagic plaques correlates with iron-stimulated IL-6/STAT3 pathway activation in macrophages

  • Biochem Biophys Res Commun. 2019 Jul 23;515(2):394-400. doi: 10.1016/j.bbrc.2019.05.123.
Bicheng Li 1 Jie Gong 2 Siqi Sheng 1 Minqiao Lu 2 Shuyuan Guo 1 Xuezhu Zhao 1 Haiyu Zhang 1 Huan Wang 1 Zhen Tian 2 Ye Tian 3
Affiliations

Affiliations

  • 1 Department of Cardiology, the First Affiliated Hospital, Cardiovascular Institute, Harbin Medical University, Harbin, 150001, P.R. China.
  • 2 Department of Pathophysiology and Key Laboratory of Cardiovascular Pathophysiology, Harbin Medical University, Key Laboratory of Cardiovascular Medicine Research (Harbin Medical University), Ministry of Education, Harbin, 150086, P.R. China.
  • 3 Department of Cardiology, the First Affiliated Hospital, Cardiovascular Institute, Harbin Medical University, Harbin, 150001, P.R. China; Department of Pathophysiology and Key Laboratory of Cardiovascular Pathophysiology, Harbin Medical University, Key Laboratory of Cardiovascular Medicine Research (Harbin Medical University), Ministry of Education, Harbin, 150086, P.R. China. Electronic address: yetian@ems.hrbmu.edu.cn.
Abstract

Intraplaque hemorrhage (IPH) promotes the rapid progression of atherosclerotic plaques, resulting in cardiovascular events in a short time. Hepcidin increases iron retention and exerts proinflammatory effects in plaques. However, hepcidin expression levels in hemorrhagic plaques remain unknown. In the present study, we evaluated hepcidin expression in hemorrhagic plaques and the underlying mechanism. To investigate hepcidin expression in hemorrhagic plaques, carotid artery plaques were collected from patients undergoing carotid endarterectomy (CEA) and apolipoprotein E-deficient mice. The hepcidin expression level was increased in the area of IPH and positively correlated with the amount of hemorrhage as shown by immunohistochemistry. Hepcidin expression in macrophages within human plaques was confirmed by immunofluorescence. Furthermore, ferric ammonium citrate (FAC) was found to induce hepcidin and interleukin-6 (IL-6) expression in THP-1 macrophages and mouse peritoneal macrophages. Subsequently, activation of the IL-6/signal transducer and activator of transcription (STAT) 3 pathway was observed in rabbit hemorrhagic plaques. Macrophages were pretreated with Antibodies that block IL-6/IL-6R interactions or STAT3 activation and dimerization inhibitor (STATTIC), and the results indicated that FAC induced hepcidin expression through the IL-6/STAT3 pathway. In conclusion, our data indicate that hepcidin levels are increased in hemorrhagic plaques, which correlates with iron-stimulated IL-6/STAT3 pathway activation in macrophages. Therefore, inhibition of the IL-6/STAT3 pathway may be a potential strategy to reduce hepcidin expression and further stabilize hemorrhagic plaques.

Keywords

Hepcidin; IL-6; Intraplaque hemorrhage; Iron; Macrophage; STAT3.

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