Circulating HMGB2 Is Associated With Angiographic Coronary Collateralization in Diabetic Patients With Chronic Total Occlusion and Impairs Vessel Growth via NLRP3

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Background: HMGB2 is reported to be strongly associated with cardiovascular diseases, but its relationship with coronary collateralization is unclear.

Methods and Results: We determined the serum HMGB2 levels in 322 patients with type 2 diabetes and coronary chronic total occlusion (CTO), and evaluated the degree of coronary collaterals by Rentrop classification (poor collaterals: Rentrop score 0 or 1; good collaterals: Rentrop score 2 or 3). Anti-HMGB2 neutralizing antibody was administered in a diabetic ischemic hindlimb mouse model, followed by laser Doppler perfusion imaging and histological examinations. Human umbilical vein endothelial cells (HUVECs) were treated with HMGB2 to assess the potential mechanisms. Serum HMGB2 decreased stepwise across Rentrop score 0 to 3 (P<0.001), with significantly higher levels in patients with poor collaterals than in those with good collaterals (P<0.001). After adjustment for various confounders, HMGB2 remained an independent factor for poor coronary collateralization (adjusted odds ratio, 1.234; 95% confidence interval, 1.136–1.340; P<0.001). In diabetic mice with hindlimb ischemia, administration of anti-HMGB2 neutralizing antibody increased blood flow restoration. HMGB2 inhibited migration and tube formation of HUVECs in a dose-dependent manner under high-glucose and hypoxic conditions, and promoted NLRP3-mediated pyroptosis.

Conclusions: Elevated circulating HMGB2 was associated with poor coronary collateralization in CTO patients with diabetes. HMGB2 impaired angiogenesis and collateral vessel growth in diabetic mice. Such effects are mediated by NLRP3.