Iron Overload Augments Angiotensin II–Induced Cardiac Fibrosis and Promotes Neointima Formation

Abstract

Background-Abnormal iron deposition may cause oxidant-induced damage in various organs. We have previously reported that continuous administration of angiotensin II to rats results in an overt iron deposition in the renal tubular epithelial cells, which may have a role in angiotensin II-induced renal damage. In the present study, we investigated the role of iron in the development of cardiac injury induced by angiotensin II. Methods and Results-Angiotensin II was continuously infused to rats at a dose of 0.7 mg/kg per day for 7 consecutive days. No iron deposits were observed in the hearts of untreated rats, whereas iron deposition was seen in the cells in the subepicardial and granulation regions after angiotensin II infusion. Concomitant administration of deferoxamine, an iron chelator, significantly reduced the extent of cardiac fibrosis, which suggests that iron deposition aggravates the cardiac fibrosis induced by angiotensin II. Iron overload caused by the administration of iron-dextran resulted in an augmentation of cardiac fibrosis and the generation of neointimal cells in the coronary artery in angiotensin II-infused rats. By contrast, neointima was not formed in the cardiac vessels in norepinephrine-infused rats with iron overload. Conclusions-Cardiac iron deposition may be involved in the development of cardiac fibrosis induced by angiotensin II.In addition, iron overload may enhance the formation of neointima under conditions of increased circulating angiotensin II but not catecholamines.

Administration of ANG II induces iron deposition and upregulation of TGF-β1 mRNA in the rat liver

“…Interestingly, however, Yokohama et al (34) have very recently reported that AT1 receptor antagonism not only suppressed the hepatic fibrosis, but also reduced the serum ferritin content. In addition, we have demonstrated that ANG II administration to rats caused deposition of iron and induction of ferritin in the heart and that AT1 receptor blockade decreased the extent of fibrosis and expression of ferritin in the heart (16). Together with the current results, it is suggested that ANG II may act to promote organ fibrosis, in part, via modulating iron homeostasis, and this can be suppressed by the AT1 receptor antagonism.…”

“…We recently demonstrated that ANG II infusion into rats causes iron deposition and the induction of ferritin expression in the kidney (14) and heart (16), which may augment the profibrotic effects of this peptide. Iron catalyzes Fenton and Haber-Weiss reactions to generate toxic hydroxyl radicals and the consequent products of lipid peroxidation.…”

Therapeutic efficacy of an angiotensin II receptor antagonist in patients with nonalcoholic steatohepatitis

“…14 Although the interaction between angiotensin II and hepatic iron overload has not been well defined, animal experiments have recently shown that chronic administration of angiotensin II induces iron deposition in the heart, leading to cardiac fibrosis, and that this effect is blocked by losartan administration. 8 As in the heart, angiotensin II may provoke hepatic iron deposition, and losartan may inhibit this action. Angiotensin II has been reported to enhance insulin resistance, and this effect was reversed by angiotensin II receptor antagonist.…”

“…Recent studies have demonstrated a crucial role of angiotensin II in the pathogenesis of hepatic fibrosis, 6 and this peptide has been shown to enhance insulin resistance and tissue iron deposition. 7,8 Administration of an antagonist of angiotensin II type 1 receptor has been shown to decrease hepatic fibrosis in rats. 6 In the present study, the effects of losartan, a selective angiotensin II type I receptor antagonist, were investigated in patients with NASH.…”

Iron Chelation Suppresses Ferritin Upregulation and Attenuates Vascular Dysfunction in the Aorta of Angiotensin II–Infused Rats

“…In previous studies, we have reported that long-term administration of angiotensin II (Ang II) in rats caused accumulation of iron in the kidney, 13,14 heart, 15 and liver, 16 and that this may play a role in regulating the gene expression and function in these organs. Thus far, little is known about whether Ang II induces aberrant iron homeostasis in the vascular tissue; however, if so, it might exacerbate the oxidant-induced vascular damage initiated by increased production of superoxide 17 generated by activated NAD(P)H oxidase.…”