Mitochondrial 8-hydroxy-2′-deoxyguanosine and coronary artery disease in patients with type 2 diabetes mellitus

Abstract

Background: Little is known about whether mitochondria 8-hydroxy-2′-deoxyguanosine (8-OHdG), a biomarker of mitochondrial DNA (mtDNA) oxidative damage, contributes to the development of coronary artery disease (CAD) in diabetic patients. Here, we explored the associations of mtDNA 8-OHdG in leukocytes with obstructive CAD, coronary stenosis severity, cardiovascular biomarkers, and 1-year adverse outcomes after coronary revascularization in patients with type 2 diabetes mellitus (T2DM). Methods: In a total of 1920 consecutive patients with T2DM who underwent coronary angiography due to symptoms of angina or angina equivalents, the presence of obstructive CAD, the number of diseased vessels with ≥ 50% stenosis, and modified Gensini score were cross-sectionally evaluated; the level of mtDNA 8-OHdG was quantified by quantitative PCR. Then, 701 of 1920 diabetic patients who further received coronary revascularization completed 1-year prospective follow-up to document major adverse cardiovascular and cerebral events (MACCEs). In vitro experiments were also performed to observe the effects of mtDNA oxidative damage in high glucose-cultured human umbilical vein endothelial cells (HUVECs). Results: Cross-sectionally, greater mtDNA 8-OHdG was associated with increased odds of obstructive CAD (odds ratio [OR] 1.38, 95% CI confidence interval 1.24-1.52), higher degree of coronary stenosis (number of diseased vessels: OR 1.29, 95% CI 1.19-1.41; modified Gensini scores: OR 1.28, 95% CI 1.18-1.39), and higher levels of C-reactive protein (β 0.18, 95% CI 0.06-0.31) after adjusting for confounders. Sensitivity analyses using propensity score matching yielded similar results. Stratification by smoking status showed that the association between mtDNA 8-OHdG and obstructive CAD was most evident in current smokers (P interation < 0.01). Prospectively, the adjusted hazards ratio per 1-SD increase in mtDNA 8-OHdG was 1.59 (95% CI 1.33-1.90) for predicting 1-year MACCEs after revascularization. In HUVECs, exposure to antimycin A, an inducer for mtDNA oxidative damage, led to adverse alterations in markers of mitochondrial and endothelia function. Conclusion: Greater mtDNA 8-OHdG in leukocytes may serve as an independent risk factor for CAD in patients with T2DM.

Redox-related biomarkers in human cardiovascular disease - classical footprints and beyond

“…All alphabetical cross references in this figure ( a, b, c … ) are linked to literature reference numbers in the figure legend. The respective references are as follows: a [ 75 ], b [ 83 ], c [ 124 ], d [ 184 ], e [ 85 ], f [ 96 ], g [ 125 ], h [ 88 ], i [ 120 ], j [ 77 ], k [ 86 ], l [ 98 ], m [ 126 ], n [ 185 ], o [ 87 ], p [ 89 ], q [ 90 ], r [ 108 ], s [ 110 ], t [ 111 ], u [ 114 ], v [ 140 ], w [ 141 ], x [ 145 , [148] , [149] , [150] , [151] , [152] ], y [ 160 ], z [ [239] , [240] , [241] ], & [ 187 ]. Open access source for body image can be found at Pixabay ( https://pixabay.com/de/photos/anatomie-frau-mensch-k%C3%B6rper-haut-254120/ ).…”

“…3 Prognostic value of classical oxidative stress markers for cardiovascular risk. ( A ) Association of markers of lipid peroxidation (isoprostane [8-iso-PGF2α] and malondialdehyde [MDA]) [ 75 , 83 , 85 ], nitro-oxidative stress (3-nitrotyrosine [3-NT]) [ 96 ], oxidative mitochondrial DNA damage (8-hydroxy-deoxyguanosine [8-OHdG]) [ 120 ] and derivatives of reactive oxygen metabolites (d-ROMs) [ 125 ] with cardiovascular risk in the comparison of healthy subjects with cardiovascular disease patients. ( B ) Associations of d-ROM levels and total thiol levels (TTL) with cardiovascular disease-specific mortality (adjusted for age and sex).…”

“…In good agreement, a further meta-analysis of six studies (446 heart failure patients and 140 controls) from the same author group showed higher levels of 8-OHdG in heart failure patients than in controls (SMD 0.89, 95% CI 0.68–1.10) with a progressive increase for higher NYHA class [ 119 ]. A recent study by Wang et al from 2020 aimed to investigate whether 8-OHdG may contribute to the incidence of CAD in 1920 patients with type 2 diabetes mellitus [ 120 ]. After multivariable adjustment, the authors reported elevated levels of 8-OHdG to be cross-sectionally related to increased odds of obstructive CAD (OR 1.38, 95% CI 1.24–1.52), higher number of diseased vessels with ≥ 50% stenosis (OR 1.29, 95% CI 1.19–1.41), modified Gensini score (OR 1.28, 95% CI 1.18–1.39) and higher levels of C-reactive protein (β 0.18, 95% CI 0.06–0.31).…”

The adverse impact of coronary artery disease on left ventricle systolic and diastolic function in patients with type 2 diabetes mellitus: a 3.0T CMR study

“…T2DM patients with CAD were classified into one-, two-, or three-vessel disease according to the number of diseased coronary arteries. The luminal diameter narrowing of left main coronary artery ≥ 50% was considered as three-vessel disease [ 17 ]. According to the method described in the literature [ 18 ], the Gensini score was calculated to assess the severity of CAD by two independent experienced cardiologists who were blinded to the clinical and procedural data.…”

Advancement in the diagnosis of mitochondrial diseases

“…The levels of MMP2 and MMP9 were increased in ST-segment elevation myocardial infarction, non-ST segment elevation myocardial infarction and unstable angina pectoris (UA) compared to the control group (P < 0.05) [140] . Also, Wang and colleagues showed that increased mtDNA 8-OHdG could increase the odds of having coronary artery disease (CAD) (OR = 1.38), coronary stenosis (OR = 1.29), and higher levels of C-reactive protein [141] . Although these findings supported the notion that mitochondrial dysfunction could contribute to the development of CVD, the exact mechanism for that association is still unknown.…”