Abstract
BackgroundLittle 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).MethodsIn 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).ResultsCross-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 (Pinteration < 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.ConclusionGreater mtDNA 8-OHdG in leukocytes may serve as an independent risk factor for CAD in patients with T2DM.
Highlights
Patients with type 2 diabetes mellitus (T2DM) exhibit a high prevalence of coronary artery disease (CAD) and cardiac deaths [1, 2]
Besides the observation that the linear association between mitochondrial DNA (mtDNA) 8-OHdG and CAD presence in patients with T2DM remained significant after adjusting for multiple cardiovascular risk factors and T2DM-related variables, we found that adding mtDNA 8-OHdG into established risk prediction models improved risk discrimination and reclassification for CAD events
Hyperglycemia may induce the interaction of mtDNA oxidative damage with inflammatory cytokine release, causing apoptosis of monocytes, T2DM-related endothelial dysfunction, and plaque instability [48]. In line with this evidence, we found that mtDNA 8-OHdG positively correlated with C-reactive protein (CRP) levels, a well established measure of systemic inflammation, in patients with T2DM, and that antimycin A (AMA)-induced mtDNA oxidative damage was linked to adverse alterations in markers of endothelial dysfunction and cell viability in high glucose-cultured human umbilical vein endothelial cells (HUVECs)
Summary
Patients with type 2 diabetes mellitus (T2DM) exhibit a high prevalence of coronary artery disease (CAD) and cardiac deaths [1, 2]. Little is known about whether 8-OHdG in mtDNA, a more direct marker of oxidative DNA damage, contributes to the development of CAD in patients with T2DM. 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. 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)
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