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1.
Genet Mol Res ; 14(2): 4521-31, 2015 May 04.
Article in English | MEDLINE | ID: mdl-25966225

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 factor-kB, 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.


Subject(s)
Atherosclerosis/metabolism , Diabetes Mellitus, Type 2/complications , Diabetic Foot/metabolism , HMGB1 Protein/metabolism , Amputation, Surgical , Arterial Occlusive Diseases/genetics , Arterial Occlusive Diseases/metabolism , Atherosclerosis/genetics , Biomarkers , Diabetic Foot/genetics , Diabetic Foot/surgery , Gene Expression , HMGB1 Protein/genetics , Humans , Inflammation , Oxidative Stress , Peripheral Arterial Disease/genetics , Peripheral Arterial Disease/metabolism
2.
Genet Mol Res ; 11(3): 3339-48, 2012 Sep 17.
Article in English | MEDLINE | ID: mdl-23079827

ABSTRACT

Hyperglycemia-induced reactive oxygen species production can cause diabetes and its complications, including atherosclerosis. The role of mitochondrial DNA variants and mitochondrial copy number in the pathogenesis of diabetic atherogenesis is not well understood. We examined 36 diabetic patients who had undergone amputation for diabetic foot and seven non-diabetic patients who had undergone amputation after traumatic injury. Mitochondrial DNA was extracted and used for sequencing. Single nucleotide polymorphisms (SNPs) relative to the Cambridge reference sequence were analyzed. Mitochondrial DNA copy number was quantified by real-time PCR. Twenty-one novel variants were detected in 29 diabetic patients with arterial stenosis; six of the variants were heteroplasmic, and most occurred in highly evolutionarily conserved residues. These variants were more prevalent in patients with arterial stenosis than in those without stenosis. The novel variants included four in complex I (ND1: C3477A/C, A3523A/G; ND5: C13028A/C, C13060A/C), one in complex IV (COX1: T6090A/T), and one in rRNA (12srRNA: G857G/T). Compared with non-diabetic patients, the diabetic patients had significantly less mitochondrial DNA. Furthermore, among diabetic patients with arterial stenosis, there was a significant positive correlation between mitochondrial DNA copy number and the number of total SNPs. In conclusion, we identified six novel heteroplasmic mitochondrial DNA variants among diabetic patients with arterial stenosis, and we found that diabetic atherogenesis is associated with decreased amounts of mitochondrial DNA.


Subject(s)
Atherosclerosis/genetics , DNA Copy Number Variations/genetics , DNA, Mitochondrial/genetics , Diabetes Complications/genetics , Amino Acid Sequence , Base Sequence , Conserved Sequence/genetics , DNA Mutational Analysis , Electron Transport Complex I/chemistry , Electron Transport Complex I/genetics , Electron Transport Complex IV/chemistry , Electron Transport Complex IV/genetics , Humans , Mitochondria/genetics , Mitochondrial Proteins/chemistry , Mitochondrial Proteins/genetics , Molecular Sequence Data , Polymorphism, Single Nucleotide/genetics
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