title: Hepcidin destabilizes atherosclerotic plaque via overactivating macrophages after erythrophagocytosis.
abstract: OBJECTIVE
  To explore a direct and causal relationship between vascular hepcidin and atherosclerotic plaque stability.
  
  
  RESULTS
  Accelerated atherosclerotic lesions were established by perivascular collar placement in apolipoprotein E-deficient (ApoE(-/-)) mice. Adenoviral overexpression of hepcidin in the carotid artery during plaque formation enhanced intraplaque macrophage infiltration and suppressed the contents of collagen and vascular smooth muscle cells, whereas hepcidin shRNA treatment exerts opposite effects. The overexpression or knockdown of hepcidin did not affect plaque lipid deposition but increased or decreased oxidized low-density lipoprotein (ox-LDL) levels within intraplaque macrophages. In cultured macrophages, ox-LDL not only increased reactive oxygen species formation, inflammatory cytokine production, and apoptosis but also upregulated hepcidin expression. However, hepcidin did not exaggerate the ox-LDL-induced activation of macrophages until an onset of erythrophagocytosis. Whereas hepcidin was critical for the upregulation of L-ferritin and H-ferritin in both ox-LDL-treated erythrophagocytosed macrophages and atherosclerotic plaques, the adding of iron chelators suppressed the intracellular lipid accumulation, reactive oxygen species formation, inflammatory cytokine expression, and apoptosis in erythrophagocytosed macrophages.
  
  
  CONCLUSIONS
  Hepcidin promotes plaque destabilization partly by exaggerating inflammatory cytokine release, intracellular lipid accumulation, oxidative stress, and apoptosis in the macrophages with iron retention.
authors.affiliation: Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Shandong University, Jinan, Shandong, China.
authors.forename: Jing Jing
authors.initials: JJ
authors.lastname: Li
authors.forename: Xiao
authors.initials: X
authors.lastname: Meng
authors.forename: Hai Peng
authors.initials: HP
authors.lastname: Si
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.forename: Hui Xia
authors.initials: HX
authors.lastname: Lv
authors.forename: Yu Xia
authors.initials: YX
authors.lastname: Zhao
authors.forename: Jian Min
authors.initials: JM
authors.lastname: Yang
authors.forename: Mei
authors.initials: M
authors.lastname: Dong
authors.forename: Kai
authors.initials: K
authors.lastname: Zhang
authors.forename: Su Xia
authors.initials: SX
authors.lastname: Liu
authors.forename: Xue Qiang
authors.initials: XQ
authors.lastname: Zhao
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.forename: Xiao Ling
authors.initials: XL
authors.lastname: Liu
authors.forename: Tai Xing
authors.initials: TX
authors.lastname: Cui
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000096:biosynthesis / Q000235:genetics*; D001057:Apolipoproteins E / Q000172:deficiency; D017209:Apoptosis; D002478:Cells, Cultured; D057899:Cytophagocytosis; D004195:Disease Models, Animal; D018450:Disease Progression; D004912:Erythrocytes / Q000473:pathology*; D005786:Gene Expression Regulation; D064451:Hepcidins; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D058226:Plaque, Atherosclerotic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D023181:Antimicrobial Cationic Peptides; D001057:Apolipoproteins E; C579599:Hamp protein, mouse; D064451:Hepcidins; D012333:RNA, Messenger