Expression of high-mobility group box protein 1 in diabetic foot atherogenesis

Abstract

ABSTRACT. The role of high mobility group box 1 (HMGB1) has been demonstrated in stroke and coronary artery disease but not in peripheral arterial occlusive disease (PAOD). The pathogenesis of HMGB1 in acute and chronic vascular injury is also not well understood. We hypothesized that HMGB1 induces inflammatory markers in diabetic PAOD patients. We studied 36 diabetic patients, including 29 patients with PAOD, who had undergone amputation for diabetic foot and 7 nondiabetic patients who had undergone amputation after traumatic injury. Expression of HMGB1 and inflammatory markers were quantified using immunohistochemical staining. Mitochondrial DNA copy number was quantified using real-time polymerase chain reaction. Compared with that in the traumatic amputation group, HMGB1 expression in vessels was significantly higher in the diabetes and diabetic PAOD groups. In all subjects, arterial stenosis grade was positively correlated with the expression levels of HMGB1, 8-hydroxyguanosine, malondialdehyde, vascular cell adhesion molecule 1, and inflammatory markers CD3, and CD68 in both the intima and the media of vessels. Furthermore, HMGB1 expression level was positively correlated with 8-hydroxyguanosine, vascular cell adhesion molecule 1, nuclear factorkB, CD3, and CD68 expression. Within the PAOD subgroup, subjects with HMGB1 expression had higher expression of the autophagy marker LC3A/B and higher mitochondrial DNA copy number. HMGB1 may be an inflammatory mediator with roles in oxidative damage and proinflammatory and inflammatory processes in diabetic atherogenesis. Moreover, it may have dual effects by compensating for increased mitochondrial DNA copy number and increased autophagy marker expression.

High Mobility Group Box-1: A Missing Link between Diabetes and Its Complications

“…In line with our studies, Feng and colleagues indicated that the interaction of HMGB-1 and its receptors triggered the oxidative stress in endothelial dysfunction [34]; similarly, serum HMGB-1 concentration was shown to reflect endothelial dysfunction in diabetes [22]. Recently, the increased HMGB-1 expression was found to be positively correlated with arterial stenosis, oxidative stress, and inflammation in diabetic patients with peripheral arterial occlusive disease [46]. In vitro experiment showed that microRNA-24 attenuated high-glucose-induced vascular smooth muscle cell proliferation and migration by targeting HMGB-1.…”

Emerging Role of High Mobility Group Box-1 in Thrombosis-Related Diseases

“…This notion was strongly supported by a recent study showing higher serum HMGB-1 levels in patients with type 2 diabetes affected by PAD [93]. Furthermore, the expression of HMGB-1 increased in diabetic foot atherogenesis and arteriosclerosis obliterans [94,95].…”

High Mobility Group B-1 (HMGB-1) Promotes Apoptosis of Macrophage-Derived Foam Cells by Inducing Endoplasmic Reticulum Stress

“…In apolipoprotein E-deficient (apoE -/-) mice fed high-fat diet, treatment with neutralizing antibodies against HMGB-1 significantly prevented the development of atherosclerosis [10]. Further evidence revealed the critical role of HMGB-1 in human atherosclerosis lesions from the aorta, indicating high expression of HMGB-1 in carotid arteries [11], coronary arteries [12], and peripheral vessels [13]. In addition, macrophages have been considered to be primarily responsible for HMGB-1 expression in atherosclerosis [14], suggesting that the protein might promote macrophage-derived foam cells in plaques.…”