OBJECTIVE—Mitochondrial DNA (mtDNA) damage is present in murine and human atherosclerotic plaques. However, whether endogenous levels of mtDNA damage are sufficient to cause mitochondrial dysfunction ...and whether decreasing mtDNA damage and improving mitochondrial respiration affects plaque burden or composition are unclear. We examined mitochondrial respiration in human atherosclerotic plaques and whether augmenting mitochondrial respiration affects atherogenesis.
APPROACH AND RESULTS—Human atherosclerotic plaques showed marked mitochondrial dysfunction, manifested as reduced mtDNA copy number and oxygen consumption rate in fibrous cap and core regions. Vascular smooth muscle cells derived from plaques showed impaired mitochondrial respiration, reduced complex I expression, and increased mitophagy, which was induced by oxidized low-density lipoprotein. Apolipoprotein E–deficient (ApoE) mice showed decreased mtDNA integrity and mitochondrial respiration, associated with increased mitochondrial reactive oxygen species. To determine whether alleviating mtDNA damage and increasing mitochondrial respiration affects atherogenesis, we studied ApoE mice overexpressing the mitochondrial helicase Twinkle (Tw/ApoE). Tw/ApoE mice showed increased mtDNA integrity, copy number, respiratory complex abundance, and respiration. Tw/ApoE mice had decreased necrotic core and increased fibrous cap areas, and Tw/ApoE bone marrow transplantation also reduced core areas. Twinkle increased vascular smooth muscle cell mtDNA integrity and respiration. Twinkle also promoted vascular smooth muscle cell proliferation and protected both vascular smooth muscle cells and macrophages from oxidative stress–induced apoptosis.
CONCLUSIONS—Endogenous mtDNA damage in mouse and human atherosclerosis is associated with significantly reduced mitochondrial respiration. Reducing mtDNA damage and increasing mitochondrial respiration decrease necrotic core and increase fibrous cap areas independently of changes in reactive oxygen species and may be a promising therapeutic strategy in atherosclerosis.Arteriosclerosis, Thrombosis, and Vascular Biology is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited and is not used for commercial purposes.
Summary
Aging is the largest risk factor for cardiovascular disease, yet the molecular mechanisms underlying vascular aging remain unclear. Mitochondrial DNA (mtDNA) damage is linked to aging, but ...whether mtDNA damage or mitochondrial dysfunction is present and directly promotes vascular aging is unknown. Furthermore, mechanistic studies in mice are severely hampered by long study times and lack of sensitive, repeatable and reproducible parameters of arterial aging at standardized early time points. We examined the time course of multiple invasive and noninvasive arterial physiological parameters and structural changes of arterial aging in mice, how aging affects vessel mitochondrial function, and the effects of gain or loss of mitochondrial function on vascular aging. Vascular aging was first detected by 44 weeks (wk) of age, with reduced carotid compliance and distensibility, increased β‐stiffness index and increased aortic pulse wave velocity (PWV). Aortic collagen content and elastin breaks also increased at 44 wk. Arterial mtDNA copy number (mtCN) and the mtCN‐regulatory proteins TFAM, PGC1α and Twinkle were reduced by 44 wk, associated with reduced mitochondrial respiration. Overexpression of the mitochondrial helicase Twinkle (Tw+) increased mtCN and improved mitochondrial respiration in arteries, and delayed physiological and structural aging in all parameters studied. Conversely, mice with defective mitochondrial polymerase‐gamma (PolG) and reduced mtDNA integrity demonstrated accelerated vascular aging. Our study identifies multiple early and reproducible parameters for assessing vascular aging in mice. Arterial mitochondrial respiration reduces markedly with age, and reduced mtDNA integrity and mitochondrial function directly promote vascular aging.
Mitochondria are the cellular powerhouses, fuelling metabolic processes through their generation of ATP. However we now recognise that these organelles also have pivotal roles in producing reactive ...oxygen species (ROS) and in regulating cell death, inflammation and metabolism. Mitochondrial dysfunction therefore leads to oxidative stress, cell death, metabolic dysfunction and inflammation, which can all promote atherosclerosis. Recent evidence indicates that mitochondrial DNA (mtDNA) damage is present and promotes atherosclerosis through mitochondrial dysfunction. We will review the mechanisms that link mtDNA damage with atherosclerotic disease, and identify mitochondrial processes that may have therapeutic benefit.
•Recent evidence highlights that mitochondrial DNA damage can directly promote atherosclerosis.•Mitochondrial DNA damage leads to cell death, inflammation and altered metabolism.•Mitochondrial dysfunction may not necessarily result in increased oxidative stress.•Mitochondrial pathways may be the source of novel therapies for atherosclerosis.
Atherosclerosis is a chronic inflammatory disease of the vascular system and is the leading cause of cardiovascular diseases worldwide. Excessive generation of reactive oxygen species (ROS) leads to ...a state of oxidative stress which is a major risk factor for the development and progression of atherosclerosis. ROS are important for maintaining vascular health through their potent signalling properties. However, ROS also activate pro-atherogenic processes such as inflammation, endothelial dysfunction and altered lipid metabolism. As such, considerable efforts have been made to identify and characterise sources of oxidative stress in blood vessels. Major enzymatic sources of vascular ROS include NADPH oxidases, xanthine oxidase, nitric oxide synthases and mitochondrial electron transport chains. The production of ROS is balanced by ROS-scavenging antioxidant systems which may become dysfunctional in disease, contributing to oxidative stress. Changes in the expression and function of ROS sources and antioxidants have been observed in human atherosclerosis while in vitro and in vivo animal models have provided mechanistic insight into their functions. There is considerable interest in utilising antioxidant molecules to balance vascular oxidative stress, yet clinical trials are yet to demonstrate any atheroprotective effects of these molecules. Here we will review the contribution of ROS and oxidative stress to atherosclerosis and will discuss potential strategies to ameliorate these aspects of the disease.
For any set Ω of non‐negative integers such that {0,1}⊊Ω, we consider a random Ω‐k‐tree Gn,k that is uniformly selected from all connected k‐trees of (n + k) vertices such that the number of (k + ...1)‐cliques that contain any fixed k‐clique belongs to Ω. We prove that Gn,k, scaled by (kHkσΩ)/(2n) where Hk is the kth harmonic number and σΩ > 0, converges to the continuum random tree Te. Furthermore, we prove local convergence of the random Ω‐k‐tree Gn,k∘ to an infinite but locally finite random Ω‐k‐tree G∞,k.
Accurate assessment of iron and vitamin A status is needed to inform public health decisions, but most population-level iron and vitamin A biomarkers are independently influenced by inflammation.
We ...aimed to assess the reproducibility of the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) regression approach to adjust iron ferritin, soluble transferrin receptor (sTfR) and vitamin A retinol-binding protein (RBP), retinol biomarkers for inflammation (α-1-acid glycoprotein and C-reactive protein).
We conducted a sensitivity analysis comparing unadjusted and adjusted estimates of iron and vitamin A deficiency using the internal-survey regression approach from BRINDA phase 1 (16 surveys in children, 10 surveys in women) and 13 additional surveys for children and women (BRINDA phase 2).
The relations between inflammation and iron or vitamin A biomarkers were statistically significant except for vitamin A biomarkers in women. Heterogeneity of the regression coefficients across surveys was high. Among children, internal-survey adjustments increased the estimated prevalence of depleted iron stores (ferritin <12 µg/L) by a median of 11 percentage points (pp) (24 pp and 9 pp in BRINDA phase 1 and phase 2, respectively), whereas estimates of iron-deficient erythropoiesis (sTfR >8.3 mg/L) decreased by a median of 15 pp (15 pp and 20 pp in BRINDA phase 1 and phase 2, respectively). Vitamin A deficiency (RBP <0.7 µmol/L or retinol <0.7 µmol/L) decreased by a median of 14 pp (18 pp and 8 pp in BRINDA phase 1 and phase 2, respectively) in children. Adjustment for inflammation in women resulted in smaller differences in estimated iron deficiency than in children.
Our findings are consistent with previous BRINDA conclusions that not accounting for inflammation may result in an underestimation of iron deficiency and overestimation of vitamin A deficiency. Research is needed to understand the etiology of the heterogeneity in the regression coefficients before a meta-analyzed regression correction can be considered.
We study random unlabelled k-trees by combining the colouring approach by Gainer-Dewar and Gessel (2014) with the cycle-pointing method by Bodirsky, Fusy, Kang and Vigerske (2011). Our main ...applications are Gromov–Hausdorff–Prokhorov and Benjamini–Schramm limits that describe their asymptotic geometric shape on a global and local scale as the number of (k + 1)-cliques tends to infinity.
The associations between anemia and household water source and sanitation remain unclear.
We aimed to assess the associations between anemia and household water source or sanitation in preschool ...children (PSC; age 6–59 mo) using population-based surveys from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project.
We analyzed national and subnational data from 21 surveys, representing 19 countries (n = 35,963). Observations with hemoglobin (Hb) and ≥1 variable reflecting household water source or sanitation were included. Anemia was defined as an altitude-adjusted Hb concentration <110 g/L. Household water source and sanitation variables were dichotomized as “improved” or “unimproved.” Poisson regressions with robust variance estimates were conducted for each survey, adjusting for child sex, age, household socioeconomic status, maternal education, and type of residence.
Access to an improved water source and improved sanitation ranged from 29.9% (Burkina Faso) to 98.4% (Bangladesh, 2012), and from 0.2% (Kenya, 2007) to 97.4% (Philippines), respectively. Prevalence of anemia ranged from 20.1% (Nicaragua) to 83.5% (Bangladesh, 2010). Seven surveys showed negative associations between anemia and improved sanitation. Three surveys showed association between anemia and improved water, with mixed directions. Meta-analyses suggested a protective association between improved household sanitation and anemia adjusted prevalence ratio (aPR) = 0.88; 95% CI: 0.79, 0.98, and no association between improved household water and anemia (aPR = 1.00; 95% CI: 0.91, 1.10). There was heterogeneity across surveys for sanitation (P< 0.01; I2 = 66.3%) and water (P< 0.01; I2 = 55.8%).
Although improved household sanitation was associated with reduced anemia prevalence in PSC in some surveys, this association was not consistent. Access to an improved water source in general had no association with anemia across surveys. Additional research could help clarify the heterogeneity between these conditions across countries to inform anemia reduction programs.
Phthalates are a group of chemicals with ubiquitous exposure worldwide. Exposures to phthalates during pregnancy may play a role in autism spectrum disorder (ASD) etiology by disrupting hormone ...levels or directly impacting fetal neurodevelopment. However, there is little research quantifying the aggregate effect of phthalates on child ASD-related behaviors.
We used data from two prospective pregnancy and birth cohorts-the Health Outcomes and Measures of the Environment (HOME) and the Early Autism Risk Longitudinal Investigation (EARLI). HOME is a general population cohort while participants in EARLI were at higher familial risk for ASD. Using quantile g-computation and linear regression models, we assessed the joint and individual associations of a mixture of six phthalate metabolites during pregnancy with child ASD-related traits measured by Social Responsiveness Scale (SRS) scores at ages 3-8 years.
Our analyses included 271 participants from HOME and 166 participants from EARLI. There were imprecise associations between the phthalate mixture and SRS total raw scores in HOME (difference in SRS scores per decile increase in every phthalate = 1.3; 95% confidence interval CI = -0.2, 2.8) and EARLI (difference in SRS scores per decile increase in every phthalate = -0.9; 95% CI = -3.5, 1.7).
The cohort-specific effect sizes of the pthalates-SRS associations were small and CIs were imprecise. These results suggest that if there are associations between phthalate metabolites during pregnancy and child SRS scores, they may differ across populations with different familial liabilities. Further studies with larger sample sizes are warranted.
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