Investigation of advanced glycosylation end products, NF-κB activation, Nrf-2 rs35652124, rs6721961 regions on endoplasmic reticulum stress in peripheral artery disease.
Kara Hatice Zühre, Yanar Fatih, Punar Şeyma, Abacı Neslihan, Ekmekçi Sema Sırma, Başar Yılmaz, Salmayenli Nihal, Özkök Elif
Abstract
PURPOSE: Oxidative stress and inflammation, and the accumulation of unfolded proteins are primary causes in the pathophysiology of peripheral artery disease (PAD), which develops in the presence of type 2 diabetes mellitus (T2DM), characterized by hyperglycemia and insulin resistance. It has been reported that the interaction between endoplasmic reticulum (ER) stress protein, protein disulfide isomerase (PDIA4), and receptor for advanced glycation end products (RAGE) make significant contributions to these processes. Our study aimed to investigate variations in the Nrf-2 rs35652124 and Nrf-2 rs6721961 polymorphic regions in PAD and examine the relationship between these variations and RAGE and PDIA4 protein levels. METHODS: The study included 114 patients aged 50-75 years with PAD from the Peripheral Vascular Surgery Outpatient Clinic of the General Surgery Department, Istanbul University Faculty of Medicine, and 50 healthy adults as a control group. RAGE and PDIA4 were examined using enzyme-linked immunosorbent assay. Nrf-2 rs35652124, rs6721961 were studied using restriction fragment length polymorphism (RFLP) following polymerase chain reaction in DNA. RESULTS: PDIA4 and RAGE were found to be highly significant (p < 0.001, for both) in PAD. PDIA4 (p = 0.002) and RAGE (p = 0.001) were found to be higher in Nrf-2 rs6721961 (-617 G/T) GG and Nrf-2 rs35652124 (-653 T/C) TT in PAD. In the receiver operating characteristic (ROC) analysis performed for PDIA4 and RAGE, significant values were obtained (p < 0.001, for both). CONCLUSION: PDIA4 and RAGE levels were found to be significantly increased in the PAD group. PDIA4 and RAGE were found to be significantly higher in patients with Nrf-2 6,721,961 G and T alleles in the PAD group. PDIA4 and RAGE were significantly higher in those with Nrf-2 rs35652124 T allele in the PAD group. It was found that diabetes might influence the Nrf-2 rs35652124 C allele in the PAD group. ROC analysis revealed that serum PDIA4 and RAGE proteins may have high sensitivity and specificity values in PAD.
Key Findings
- PDIA4 and RAGE protein levels were significantly increased in patients with peripheral artery disease (PAD).
- Higher PDIA4 and RAGE levels were associated with specific Nrf-2 polymorphisms: rs6721961 GG and rs35652124 TT genotypes in PAD patients.
- Diabetes may influence the presence of the Nrf-2 rs35652124 C allele in PAD patients.
- Receiver operating characteristic (ROC) analysis showed significant diagnostic value for PDIA4 and RAGE levels in PAD.
Clinical Significance
The study highlights the role of oxidative stress-related proteins PDIA4 and RAGE and their association with Nrf-2 genetic variants in PAD, suggesting potential biomarkers and genetic risk factors that could improve diagnosis and understanding of PAD pathophysiology, especially in diabetic patients.
Citation
Kara Hatice Zühre, Yanar Fatih, Punar Şeymaet al.. Investigation of advanced glycosylation end products, NF-κB activation, Nrf-2 rs35652124, rs6721961 regions on endoplasmic reticulum stress in peripheral artery disease. Journal of diabetes and metabolic disorders. 2026-Dec.