Dietary Iron Restriction Increases Plaque Stability in Apolipoprotein-E-Deficient Mice

Abstract

Accumulative evidence has supported the role of iron in the development of atherosclerosis. To test whether iron-mediated oxidative stress influences plaque stability, apoliporotein-E (ApoE)-deficient mice (3 months old) were placed on a chow diet or a low-iron diet for 3 months, and the abundance of interstitial collagen and the expression of the matrix degradation-associated enzyme, matrix metalloproteinase-9 (MMP-9), in vascular lesions were assessed. A low-iron diet appeared to reduce iron deposition while substantially increasing collagen content of lesions in mice. Immunostaining demonstrated lower expression of MMP-9 in lesions of iron-restricted animals. Likewise, SDS-PAGE zymography revealed lower gelatinolytic activities in aortic tissues and sera of the same group of animals. When older ApoE-deficient mice (5 months old) received a low-iron diet for 2 months, development of the lesion area was not significantly affected. However, the lesional collagen content was much higher in the iron-restricted group of animals, and MMP-9 expression in aortic tissues from the same group of mice was significantly lower. Treatment of murine J774 macrophages with increasing concentrations of ferric ammonium citrate significantly enhanced the amount of MMP-9 secreted. Together, these data indicate that decreased vascular iron content following dietary iron restriction in ApoE-deficient mice leads to lower matrix degradation capacity and increased plaque stability.

Distribution of selected elements in atherosclerotic plaques of apoE/LDLR‐double knockout mice assessed by synchrotron radiation‐induced micro‐XRF spectrometry

“…In apoE-deficient mice fed with a low-iron diet, lower expression of MMP-9 and higher collagen content in lesions were observed. 36 Oxidation of matrix macromolecules may enhance their decomposition by proteolytic enzymes. 37 Matrix degradation can be followed by lesion rupture and occlusion of the vessel.…”

Iron concentrations in atherosclerotic plaque and serum in patients with carotid atherosclerosis

“…In particular, it has been shown that removal of stored iron from the body can decrease the amount of iron deposition within atherosclerotic lesions in animal studies. Depletion of lesion iron levels in vivo by phlebotomy, systemic iron chelation treatment or dietary iron restriction reduces lesion size in these studies and increases plaque stability (10,15,27). The original formulation of the iron hypothesis did not specify a mechanism.…”

Stored Iron and Vascular Reactivity

“…21 The small but growing literature on the effects of induced iron depletion/deficiency in various experimental models of oxidative or inflammatory injury strongly supports beneficial effects of eliminating storage iron. [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40] Correlation of in vitro with in vivo endothelial iron status will be assisted by future studies into the basis for an interesting phenomenon seen in human umbilical vein endothelial cells (HUVEC). Sensitivity of HUVEC to oxidative injury or high glucose levels decreases sharply with subculture in vitro after a few passages.…”