Abstract Body: Background: Robust coronary collateral circulation (CCC) is critical for myocardial protection in chronic total occlusion (CTO). We identified Zinc-alpha2-glycoprotein (AZGP1) as differentially expressed between good (Rentrop 3) and poor (Rentrop 0) collateral CTO patients via DIA proteomics, suggesting its role in regulating collateral arteriogenesis.
Methods: We enrolled 149 CTO patients (good collateral n=80, poor n=69). Proteomics screening was validated by ELISA in an independent cohort (n=80). Hypoxia-induced endothelial cells were used to assess AZGP1 effects on proliferation, migration, and tube formation. AAV9-mediated AZGP1 overexpression was established in murine hindlimb ischemia model.
Results: AZGP1 was significantly upregulated in poor collateral group (FC>2.0, p<0.01). ELISA confirmed elevated plasma AZGP1 in poor vs good collaterals (p<0.05), negatively correlating with Rentrop grade (r=-0.42, p<0.01). ROC analysis showed AUC 0.78 (95% CI: 0.69-0.87). Recombinant AZGP1 inhibited hypoxia-induced endothelial proliferation (35%, p<0.01), migration (42%, p<0.001), and tube formation (p<0.01) via VEGFR2/PI3K/Akt suppression. In vivo, AAV9-AZGP1 overexpression impaired blood flow recovery (28% reduction, p<0.05) and capillary density (p<0.01).
Conclusions: AZGP1 functions as an endogenous inhibitor of coronary collateral formation by suppressing VEGFR2/PI3K/Akt-mediated endothelial function. Plasma AZGP1 represents a potential biomarker for collateral assessment in CTO patients.
Keywords: Chronic Total Occlusion; Collateral Circulation; Zinc-Alpha2-Glycoprotein; Angiogenesis; Endothelial Cells