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. Methods and 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-LDLtreated 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. Conclusion-Hepcidin

Serum Hepcidin Is Associated With Presence of Plaque in Postmenopausal Women of a General Population

“…These observations are consistent with those obtained in a mouse model of atherosclerosis and in macrophage cell lines, suggesting that the interaction of (locally produced) hepcidin, trapped iron, and accumulated lipids is critical for proatherosclerotic activation of macrophages, contributing to their destabilization. 22 Our results for the hepcidin/ferritin ratio, reflecting the amount of hepcidin relative to ferritin as a measure of intracellular iron, match with the latter findings, because the ratio hepcidin/ferritin showed significant association with the presence of plaque and ABI. This underscores the role of hepcidin in determining the body iron distribution and thus the interplay of hepcidin and ferritin levels in the development of atherosclerosis.…”

“…18,19 Indeed, there is some evidence for a role of hepcidin in the development of athero sclerosis from in vitro studies and studies in patients on hemodialysis. [20][21][22][23][24] However, the association of serum hepcidin with atherosclerosis has not been investigated in the general population. Here, we studied the associations of serum hepcidin and its ratios to ferritin and TS, as well as serum ferritin, serum iron, total iron-binding capacity (a proxy for transferrin), and TS (ie, iron parameters) with the following noninvasive measurements of atherosclerosis (NIMA): presence of plaque, ABI at rest and after exercise, and IMT.…”

Molecular Biology of Atherosclerosis

“…In contrast, hepcidin knock-down greatly decreased oxLDL and the cytokines in plaque macrophages (1025). In the setting of an advanced atherosclerotic plaque with secondary intraplaque hemorrhage, the potentially anti-inflammatory effects of heme are probably "too little, too late."…”

Atherosclerotic Plaque Rupture

“…Hepcidin degrades the iron transporter ferroportin 1, resulting in retention of iron, accumulation of intracellular lipids, and apoptosis of macrophages. 72 Adenoviral-overexpressed hepcidin enhanced macrophage infiltration and destabilized plaques. 72 Inhibition of hepcidin via the bone morphogenetic protein pathway in liver limits atherosclerosis progression by upregulating ABCA1 and ABCG1 (ATP-binding cassette subfamily G member 1).…”

“…72 Adenoviral-overexpressed hepcidin enhanced macrophage infiltration and destabilized plaques. 72 Inhibition of hepcidin via the bone morphogenetic protein pathway in liver limits atherosclerosis progression by upregulating ABCA1 and ABCG1 (ATP-binding cassette subfamily G member 1). 73 These reports provide mechanistic insights into how erythrophagocytosis drives lesion vulnerability.…”