An Iron-Binding Exochelin Prevents Restenosis Due to Coronary Artery Balloon Injury in a Porcine Model

Rosenthal, Eli; Bohlmeyer, Teri; Monnet, Eric; MacPhail, Catriona M.; Robertson, Alastair D.; Horwitz, Marcus A.; Burchenal, J.E.B.; Horwitz, Lawrence D.

doi:10.1161/hc4301.097194

Cited by 22 publications

(16 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While this cofactor is a bacterial product obtained from cloning of the protein in bacteria, surely a serendipitous finding, we suggest that mouse urine contains an equivalent factor. Hence Ngal is a siderophore delivery protein for the proximal tubule, and this study is one of the first to use a bacterial siderophore in vivo (62).…”

Section: Discussionmentioning

confidence: 99%

Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury

Mori¹,

Lee²,

Rapoport³

et al. 2005

J. Clin. Invest.

216

238

View full text Add to dashboard Cite

Neutrophil gelatinase-associated lipocalin (Ngal), also known as siderocalin, forms a complex with ironbinding siderophores (Ngal:siderophore:Fe). This complex converts renal progenitors into epithelial tubules.In this study, we tested the hypothesis that Ngal:siderophore:Fe protects adult kidney epithelial cells or accelerates their recovery from damage. Using a mouse model of severe renal failure, ischemia-reperfusion injury, we show that a single dose of Ngal (10 μg), introduced during the initial phase of the disease, dramatically protects the kidney and mitigates azotemia. Ngal activity depends on delivery of the protein and its siderophore to the proximal tubule. Iron must also be delivered, since blockade of the siderophore with gallium inhibits the rescue from ischemia. The Ngal:siderophore:Fe complex upregulates heme oxygenase-1, a protective enzyme, preserves proximal tubule N-cadherin, and inhibits cell death. Because mouse urine contains an Ngaldependent siderophore-like activity, endogenous Ngal might also play a protective role. Indeed, Ngal is highly accumulated in the human kidney cortical tubules and in the blood and urine after nephrotoxic and ischemic injury. We reveal what we believe to be a novel pathway of iron traffic that is activated in human and mouse renal diseases, and it provides a unique method for their treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury

Mori¹,

Lee²,

Rapoport³

et al. 2005

J. Clin. Invest.

216

238

View full text Add to dashboard Cite

show abstract

“…A link between iron and the development of atherosclerosis has been the subject of debate for more than two decades. 4,26 Recent studies have shown that administration of an iron-chelating agent suppresses neointimal formation in the balloon-injured porcine artery 27 and that an iron-deficient diet blocks atherogenesis in atherosclerosisprone animal models. 5 These findings indicate that iron is involved in the generation of vascular lesions.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2002

View full text Add to dashboard Cite

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.

show abstract

“…Both coronary artery sections are at the same magnification. Reprinted with permission from Rosenthal et al (52). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars a common complication of balloon angioplasty.…”

Section: Restenosismentioning

confidence: 99%

“…To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars a common complication of balloon angioplasty. The potential usefulness of desferri-exochelins for prevention of restenosis that is associated with coronary artery angioplasty was tested in a pig model (52). Anesthetized pigs subjected to overstretch coronary artery injury with coronary angioplasty balloons develop stenosis within a month.…”

Section: Restenosismentioning

confidence: 99%

“…Such disruption is necessary to induce abnormal vascular cell growth and local restenosis in animal models (50). Histological analysis using an injury score by two investigators blinded as to the treatment group concluded that desferriExochelin 772SM injected at the angioplasty site immediately after balloon inflation caused an absolute reduction in the degree of vascular injury present one month later (52). Typical examples of a desferri-Exochelin 772SM-treated and a vehicletreated coronary artery are shown in Figure 11.…”

Section: Restenosismentioning

confidence: 99%

See 1 more Smart Citation

The Exochelins of Pathogenic Mycobacteria: Unique, Highly Potent, Lipid- and Water-Soluble Hexadentate Iron Chelators with Multiple Potential Therapeutic Uses

Horwitz

2014

Antioxidants & Redox Signaling

Self Cite

View full text Add to dashboard Cite

Significance: Exochelins are lipid-and water-soluble siderophores of Mycobacterium tuberculosis with unique properties that endow them with exceptional pharmacologic utility. Exochelins can be utilized as probes to decipher the role of iron in normal and pathological states, and, since they rapidly cross cell membranes and chelate intracellular iron with little or no toxicity, exochelins are potentially useful for the treatment of a number of iron-dependent pathological phenomena. Recent Advances: In animal models, exochelins have been demonstrated to have promise for the treatment of transfusion-related iron overload, restenosis after coronary artery angioplasty, cancer, and oxidative injury associated with acute myocardial infarction and transplantation. Critical Issues: To be clinically effective, iron chelators should be able to rapidly enter cells and chelate iron at key intracellular sites. Desferri-exochelins, and other lipid-soluble chelators, can readily cross cell membranes and remove intracellular free iron; whereas deferoxamine, which is lipid insoluble, cannot do so. Clinical utility also requires that the chelators be nontoxic, which, we hypothesize, includes the capability to prevent iron from catalyzing free radical reactions which produce OH or other reactive oxygen species. Lipid-soluble iron chelators currently available for clinical application are bidentate (deferiprone) or tridentate (desferasirox) molecules that do not block all six sites on the iron molecule capable of catalyzing free radical reactions. In contrast, desferriexochelins are hexadentate molecules, and by forming a one-to-one binding relationship with iron, they prevent free radical reactions. Future Directions: Clinical studies are needed to assess the utility of desferri-exochelins in the treatment of iron-dependent pathological disorders. Antioxid. Redox Signal. 21, 2246-2261.

show abstract

An Iron-Binding Exochelin Prevents Restenosis Due to Coronary Artery Balloon Injury in a Porcine Model

Cited by 22 publications

References 33 publications

Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury

Endocytic delivery of lipocalin-siderophore-iron complex rescues the kidney from ischemia-reperfusion injury

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

The Exochelins of Pathogenic Mycobacteria: Unique, Highly Potent, Lipid- and Water-Soluble Hexadentate Iron Chelators with Multiple Potential Therapeutic Uses

Contact Info

Product

Resources

About