Figure 8

NARFL Polymorphisms are Susceptible Sites of Vascular Endothelial Dysfunction Diseases. A) Among the seven tagSNPs of NARFL rs61112891, rs2071952, rs117952680, rs9928077, rs3752556, rs11248948 and chr16‐731143, the frequency distribution of four SNP genotypes rs1179252680, rs2071952, rs61112891 and chr16‐731143, was statistically different between cases and controls (rs1179252680 (p < 0.001), rs61112891 (p < 0.01), rs2071952 (p < 0.05) and chr16‐731143 (p < 0.05)). The OR values of rs1179252680, rs2071952 and rs61112891 were greater than 1, while the OR value of chr16‐731143 was less than 1. B) The genotype frequency distribution was further analyzed between seven tagSNPs and patients with pulmonary hypertension, neurodegenerative diseases, epilepsy, systemic lupus erythematosus, rheumatoid and arteritis. C) Mechanism summary diagram: under normal circumstances, NARFL transfers the ISC synthesized in mitochondria to CTC composed of CIAO1, MIP18 and MMS19 through CIAO1, and imparts the ISC into specific apo proteins to form mature ferrithionein and maintain intracellular iron homeostasis. When NARFL is absent, NARFL cannot transfer the ISC synthesized by mitochondria to CTC, thereby preventing the formation of mature ferrithionein (ACO1). IRP1 increases the expression of TFR1 and inhibits the expression of Ferritin, resulting in increased iron intake. At this time, there is not enough ferritin to bind Fe and store it normally. As a result, intracellular iron ions increase and oxidative stress is enhanced via the Fenton reaction. At the same time, SCL7A11 and GPX4 are down‐regulated, and the synthesis of cytoplasmic glutathione and glutamine is reduced. This further increases the production of reactive oxygen species, activates lipid peroxidation, and induces iron death in vascular endothelial cells, leading to vascular endothelial dysfunction. Statistical significance was assessed using one‐way ANOVA with Tukey's multiple comparison correction. ns, not significant; *p < 0.05; **p < 0.01; ***p < 0.001.