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    ABSTRACT: Mitochondrial DNA (mtDNA) damage occurs in both circulating cells and the vessel wall in human atherosclerosis. However it is unclear whether mtDNA damage directly promotes atherogenesis or is a consequence of tissue damage, which cell types are involved, and whether its effects are only mediated through reactive oxygen species (ROS). MtDNA damage occurred early in the vessel wall in Apolipoprotein E null (ApoE(-/-)) mice, before significant atherosclerosis developed. MtDNA defects were also identified in circulating monocytes and liver, and associated with mitochondrial dysfunction. To determine whether mtDNA damage directly promotes atherosclerosis, we studied ApoE(-/-) mice deficient for mitochondrial polymerase-γ proofreading activity (polG(-/-)/ApoE(-/-)). polG(-/-)/ApoE(-/-) mice showed extensive mtDNA damage and defects in oxidative phosphorylation, but no increase in ROS. polG(-/-)/ApoE(-/-) mice showed increased atherosclerosis, associated with impaired proliferation and apoptosis of vascular smooth muscle cells, and hyperlipidemia. Transplantation with polG(-/-)/ApoE(-/-) bone marrow increased features of plaque vulnerability, and polG(-/-)/ApoE(-/-) monocytes showed increased apoptosis and inflammatory cytokine release. To examine mtDNA damage in human atherosclerosis, we assessed mtDNA adducts in plaques, and in leukocytes from patients who had undergone virtual histology intravascular ultrasound characterization of coronary plaques. Human atherosclerotic plaques showed increased mtDNA damage compared with normal vessels; in contrast, leukocyte mtDNA damage was associated with higher-risk plaques but not plaque burden. We show that mtDNA damage in vessel wall and circulating cells is widespread, causative and indicates higher risk in atherosclerosis. Protection against mtDNA damage and improvement of mitochondrial function are potential areas for new therapeutics.
    Circulation 07/2013;
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    ABSTRACT: Necrosis can induce profound inflammation or be clinically silent. However, the mechanisms underlying such tissue specificity are unknown. Interleukin-1α (IL-1α) is a key danger signal released upon necrosis that exerts effects on both innate and adaptive immunity and is considered to be constitutively active. In contrast, we have shown that necrosis-induced IL-1α activity is tightly controlled in a cell type-specific manner. Most cell types examined expressed a cytosolic IL-1 receptor 2 (IL-1R2) whose binding to pro-IL-1α inhibited its cytokine activity. In cell types exhibiting a silent necrotic phenotype, IL-1R2 remained associated with pro-IL-1α. Cell types possessing inflammatory necrotic phenotypes either lacked IL-1R2 or had activated caspase-1 before necrosis, which degraded and dissociated IL-1R2 from pro-IL-1α. Full IL-1α activity required cleavage by calpain after necrosis, which increased its affinity for IL-1 receptor 1. Thus, we report a cell type-dependent process that fundamentally governs IL-1α activity postnecrosis and the mechanism allowing conditional release of this blockade.
    Immunity 02/2013; 38(2):285-295.
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    ABSTRACT: BACKGROUND: Vascular smooth muscle cells (VSMCs) in human atherosclerosis manifest extensive DNA damage and activation of the DNA damage response (DDR), a pathway that coordinates cell cycle arrest and DNA repair, or can trigger apoptosis or cell senescence. Sirtuin 1 deacetylase (SIRT1) regulates cell ageing and energy metabolism, and regulates the DDR through multiple targets. However, the direct role of SIRT1 in atherosclerosis and how SIRT1 in VSMCs might regulate atherosclerosis are unknown. METHODS AND RESULTS: SIRT1 expression was reduced in human atherosclerotic plaques and VSMCs both derived from plaques and undergoing replicative senescence. SIRT1 inhibition reduced DNA repair and induced apoptosis, partly through reduced activation of the repair protein Nijmegen Breakage Syndrome-1 (NBS1) but not p53. Fat feeding reduced SIRT1 and induced DNA damage in VSMCs. VSMCs from mice expressing inactive truncated SIRT1 (Δex4) showed increased oxidized LDL-induced DNA damage and senescence. ApoE(-/-) mice expressing SIRT1(Δex4) only in SMCs demonstrated increased DDR activation and apoptosis, increased atherosclerosis, reduced relative fibrous cap thickness and medial degeneration. CONCLUSIONS: SIRT1 is reduced in human atherosclerosis and is a critical regulator of the DDR and survival in VSMCs. VSMC SIRT1 protects against DNA damage, medial degeneration and atherosclerosis.
    Circulation 12/2012;
  • Atherosclerosis 12/2012; 225(2):e6.
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    ABSTRACT: BACKGROUND: The epigenomes of healthy and diseased human hearts were recently examined by genome-wide DNA methylation profiling. Repetitive elements, heavily methylated in post-natal tissue, have variable methylation profiles in cancer but methylation of repetitive elements in the heart has never been examined. RESULTS: We analyzed repetitive elements from all repeat families in human myocardial samples, and found that satellite repeat elements were significantly hypomethylated in end-stage cardiomyopathic hearts relative to healthy normal controls. Satellite repeat elements are almost always centromeric or juxtacentromeric, and their overexpression correlates with disease aggressiveness in cancer. Similarly, we found that hypomethylation of satellite repeat elements correlated with up to 27-fold upregulation of the corresponding transcripts in end-stage cardiomyopathic hearts. No other repeat family exhibited differential methylation between healthy and cardiomyopathic hearts, with the exception of the Alu element SINE1/7SL, for which a modestly consistent trend of increased methylation was observed. CONCLUSIONS: Satellite repeat element transcripts, a form of non-coding RNA, have putative functions in maintaining genomic stability and chromosomal integrity. Further studies will be needed to establish the functional significance of these non-coding RNAs in the context of heart failure.
    Genome biology 10/2012; 13(10):R90.
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    ABSTRACT: Cardiac resynchronization therapy is demonstrated to be effective in patients with advanced heart failure. Correcting mechanical dyssynchrony is proposed as the predominant mechanism of response. Achieving optimum left ventricular lead position, at the site of maximal mechanical dyssynchrony but away from transmural scar, is identified as one of the main determinants of both symptomatic and prognostic benefit. Strategies employing multimodality cardiac imaging techniques have been used to identify this optimal pacing site, in addition to any potential anatomical limitations to successful implantation. Speckle tracking echocardiography offers prospective lead targeting, incorporating pathophysiological determinants of cardiac resynchronization therapy response. This review considers the key factors in defining optimum left ventricular lead location, emphasizing the role of myocardial scar. The use of speckle tracking echocardiography and the potential for this technique to be incorporated into routine practice to guide the implant strategy in an individual patient is discussed.
    Expert Review of Medical Devices 09/2012; 9(5):521-36.
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    ABSTRACT: Caffeine remains one of the most widely consumed drugs in the world. Caffeine has multiple actions, including inhibition of the DNA damage response, and its metabolites, 1-methylxanthine and 1-methyluric acid, are potent antioxidants. Combined, these properties can exert direct effects on cell proliferation, cell death, inflammation, and DNA repair, all important processes that occur in atherosclerosis. We first examined the effects of caffeine on mouse vascular smooth muscle cells. Caffeine inhibited activation of the DNA damage response regulator ataxia telangiectasia mutated protein and its downstream targets. Caffeine delayed DNA repair, had a concentration-dependent effect on cell proliferation, and protected against apoptosis. In vitro caffeine reduced oxygen consumption and decreased generation of reactive oxygen species. In vivo caffeine reduced DDR activation in vascular and nonvascular tissues, reduced reactive nitrogen species and serum levels of the DNA adduct 8-oxo-guanine, and inhibited atherogenesis in fat-fed ApoE(-/-) mice. Reduction in atherosclerosis was independent of the effects on blood pressure and serum lipids but associated with reduced cell proliferation and ataxia telangiectasia mutated protein activation. The Methyl Xanthine caffeine inhibits the DNA damage response in vitro and in vivo, regulates both cell proliferation and apoptosis after DNA damage, inhibits reactive species, and reduces atherogenesis in ApoE(-/-) mice.
    Arteriosclerosis Thrombosis and Vascular Biology 08/2012; 32(10):2461-7.
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    ABSTRACT: Cardiovascular disease continues to be a major cause of morbidity and mortality in patients with Type 2 Diabetes Mellitus. Whilst a focus on improved glucose control and HbA1c has led to a reduction in the progression and development of microvascular complications, the potential for this strategy to reduce cardiovascular event rates is less clearly defined. Identification of the incretin axis has facilitated the development of several novel therapeutic agents which target glucagon-like peptide-1 (GLP-1) pathways. The effects on glucose homeostasis are now established, but there is also now an increasing body of evidence to support a number of pleiotropic effects on the heart that may have the potential to influence cardiovascular outcomes. In this article, we review myocardial energy metabolism with particular emphasis on the potential benefits associated with a shift towards increased glucose utilisation and present the pre-clinical and clinical evidence regarding incretin effects on the heart. In addition we discuss the potential mechanism of action and benefit of drugs that modulate GLP-1 in patients with type 2 diabetes mellitus and coronary artery disease.
    Cardiovascular & hematological agents in medicinal chemistry 07/2012;
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    ABSTRACT: Atherosclerosis is classed as a disease of aging, such that increasing age is an independent risk factor for the development of atherosclerosis. Atherosclerosis is also associated with premature biological aging, as atherosclerotic plaques show evidence of cellular senescence characterized by reduced cell proliferation, irreversible growth arrest and apoptosis, elevated DNA damage, epigenetic modifications, and telomere shortening and dysfunction. Not only is cellular senescence associated with atherosclerosis, there is growing evidence that cellular senescence promotes atherosclerosis. This review examines the pathology of normal vascular aging, the evidence for cellular senescence in atherosclerosis, the mechanisms underlying cellular senescence including reactive oxygen species, replication exhaustion and DNA damage, the functional consequences of vascular cell senescence, and the possibility that preventing accelerated cellular senescence is a therapeutic target in atherosclerosis.
    Circulation Research 07/2012; 111(2):245-59.
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    ABSTRACT: The goal of this study was to assess the role of B-cell activating factor (BAFF) receptor in B-cell regulation of atherosclerosis. Male LDL receptor-deficient mice (Ldlr(-/-)) were lethally irradiated and reconstituted with either wild type or BAFF receptor (BAFF-R)-deficient bone marrow. After 4 weeks of recovery, mice were put on a high-fat diet for 6 or 8 weeks. BAFF-R deficiency in bone marrow cells led to a marked reduction of conventional mature B2 cells but did not affect the B1a cell subtype. This was associated with a significant reduction of dendritic cell activation and T-cell proliferation along with a reduction of IgG antibodies against malondialdehyde-modified low-density lipoprotein. In contrast, serum IgM type antibodies were preserved. Interestingly, BAFF-R deficiency was associated with a significant reduction in atherosclerotic lesion development and reduced numbers of plaque T cells. Selective BAFF-R deficiency on B cells led to a similar reduction in lesion size and T-cell infiltration but in contrast did not affect dendritic cell activation. BAFF-R deficiency in mice selectively alters mature B2 cell-dependent cellular and humoral immune responses and limits the development of atherosclerosis.
    Arteriosclerosis Thrombosis and Vascular Biology 03/2012; 32(7):1573-6.
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