Haploinsufficiency of Transferrin Receptor 1 Impairs Angiogenesis with Reduced Mitochondrial Complex I in Mice with Limb Ischemia

Keisuke Okuno, Yoshiro Naito, Seiki Yasumura, Hisashi Sawada, Masanori Asakura, Tohru Masuyama, Masaharu Ishihara

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Limb ischemia (LI) is a major consequence of peripheral artery disease (PAD) with a high mortality rate. Iron is an essential mineral to maintain physiological function of multiple organs. Intracellular iron transport is regulated by transferrin receptor 1 (TfR1). Although increase in serum ferritin levels has been reported in PAD patients, the mechanism of iron metabolism in LI is still unclear. The aim of this study is to investigate whether TfR1 deletion attenuates LI formation. To generate LI, the left femoral artery of 8–10 week-old C57BL6/J male mice was ligated. Adductor muscles were harvested at 28 days after surgery to investigate iron metabolism. The level of ferritin, intracellular iron storage protein, was higher in ischemic adductor muscles compared to non-ischemic adductor muscles. Level of intracellular iron transport protein, TfR1, was decreased in ischemic adductor muscles. LI was then generated in TfR1 heterozygous deleted mice (TfR1+/−) to examine whether TfR1 contributes to the pathophysiology of LI. Laser Doppler blood flowmetry revealed that blood flow recovery was attenuated in TfR1+/− mice compared to wild type (WT) littermates, along with decreased expression of ferritin and CD31 in ischemic adductor muscles. Since iron is used for energy production in mitochondria, we then assessed mitochondrial complexes in the ischemic adductor muscle. Of interest, expression of mitochondrial complex I, but not complexes II, III, and V in ischemic adductor muscles was significantly reduced in TfR1+/− mice compared to WT mice. Haploinsufficiency of TfR1 attenuated angiogenesis via reduction of mitochondrial complex I in LI in mice.

Original languageEnglish
Article number13658
JournalScientific Reports
Issue number1
StatePublished - Dec 1 2019

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© 2019, The Author(s).

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